Analogues of GLP-1

ABSTRACT

The present invention is directed to peptide analogues of glucagon-like peptide-1, the pharmaceutically-acceptable salts thereof, to methods of using such analogues to treat mammals and to pharmaceutical compositions useful therefor comprising said analogues.

BACKGROUND OF THE INVENTION

The present invention is directed to peptide analogues of glucagon-like peptide-1, the pharmaceutically-acceptable salts thereof, to methods of using such analogues to treat mammals and to pharmaceutical compositions useful therefor comprising said analogues.

Glucagon-like peptide-1 (7-36) amide (GLP-1) is synthesized in the intestinal L-cells by tissue-specific post-translational processing of the glucagon precursor preproglucagon (Varndell, J. M., et al., J. Histochem Cytochem, 1985:33:1080-6) and is released into the circulation in response to a meal. The plasma concentration of GLP-1 rises from a fasting level of approximately 15 pmol/L to a peak postprandial level of 40 pmol/L. It has been demonstrated that, for a given rise in plasma glucose concentration, the increase in plasma insulin is approximately threefold greater when glucose is administered orally compared with intravenously (Kreymann, B., et al., Lancet 1987:2, 1300-4). This alimentary enhancement of insulin release, known as the incretin effect, is primarily humoral and GLP-1 is now thought to be the most potent physiological incretin in humans. In addition to the insulinotropic effect, GLP-1 suppresses glucagon secretion, delays gastric emptying (Wettergren A., et al., Dig Dis Sci 1993:38:665-73) and may enhance peripheral glucose disposal (D'Alessio, D. A. et al., J. Clin Invest 1994:93:2293-6).

In 1994, the therapeutic potential of GLP-1 was suggested following the observation that a single subcutaneous (s/c) dose of GLP-1 could completely normalize postprandial glucose levels in patients with non-insulin-dependent diabetes mellitus (NIDDM) (Gutniak, M. K., et al., Diabetes Care 1994:17:1039-44). This effect was thought to be mediated both by increased insulin release and by a reduction in glucagon secretion. Furthermore, an intravenous infusion of GLP-1 has been shown to delay postprandial gastric emptying in patients with NIDDM (Williams, B., et al., J. Clin Endo Metab 1996:81:327-32). Unlike sulphonylureas, the insulinotropic action of GLP-1 is dependent on plasma glucose concentration (Holz, G. G. 4^(th), et al., Nature 1993:361:362-5). Thus, the loss of GLP-1-mediated insulin release at low plasma glucose concentration protects against severe hypoglycemia. This combination of actions gives GLP-1 unique potential therapeutic advantages over other agents currently used to treat NIDDM.

Numerous studies have shown that when given to healthy subjects, GLP-1 potently influences glycemic levels as well as insulin and glucagon concentrations (Orskov, C, Diabetologia 35:701-711, 1992; Holst, J. J., et al., Potential of GLP-1 in diabetes management in Glucagon III, Handbook of Experimental Pharmacology, Lefevbre P J, Ed. Berlin, Springer Verlag, 1996, p. 311-326), effects which are glucose dependent (Kreymann, B., et al., Lancet ii: 1300-1304, 1987; Weir, G. C., et al., Diabetes 38:338-342, 1989). Moreover, it is also effective in patients with diabetes (Gutniak, M., N. Engl J Med 226:1316-1322, 1992; Nathan, D. M., et al., Diabetes Care 15:270-276, 1992), normalizing blood glucose levels in type 2 diabetic subjects (Nauck, M. A., et al., Diagbetologia 36:741-744, 1993), and improving glycemic control in type 1 patients (Creutzfeldt, W. O., et al., Diabetes Care 19:580-586, 1996), raising the possibility of its use as a therapeutic agent.

GLP-1 is, however, metabolically unstable, having a plasma half-life (t_(1/2)) of only 1-2 min in vivo. Exogenously administered GLP-1 is also rapidly degraded (Deacon, C. F., et al., Diabetes 44:1126-1131, 1995). This metabolic instability limits the therapeutic potential of native GLP-1. Hence, there is a need for GLP-1 analogues that are more active or are more metabolically stable than native GLP-1.

SUMMARY OF THE INVENTION

In one aspect, the present invention is directed to a compound of formula (I), (R²R³)-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵ -A¹⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵-A²⁶-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-A³³-A³⁴-A³⁵-A³⁶-A³⁷-A³⁸-A³⁹-R¹,   (I) wherein

-   -   A⁷ is L-His, Ura, Paa, Pta, Amp, Tma-His, des-amino-His, or         deleted;     -   A⁸ is Ala, D-Ala, Aib, Acc, N-Me-Ala, N-Me-D-Ala or N-Me-Gly;     -   A⁹ is Glu, N-Me-Glu, N-Me-Asp or Asp;     -   A¹⁰ is Gly, Acc, β-Ala or Aib;     -   A¹¹ is Thr or Ser;     -   A¹² is Phe, Acc, Aic, Aib, 3-Pal, 4-Pal, β-Nal, Cha, Trp or         X¹-Phe;     -   A¹³ is Thr or Ser;     -   A¹⁴ is Ser or Aib;     -   A¹⁵ is Asp or Glu;     -   A¹⁶ is Val, Acc, Aib, Leu, Ile, Tle, Nle, Abu, Ala or Cha;     -   A¹⁷ is Ser or Thr;     -   A¹⁸ is Ser or Thr;     -   A¹⁹ is Tyr, Cha, Phe, 3-Pal, 4-Pal, Acc, β-Nal or X¹-Phe;     -   A²⁰ is Leu, Acc, Aib, Nle, Ile, Cha, Tle, Val, Phe or X¹-Phe;     -   A²¹ is Glu or Asp;     -   A²² is Gly, Acc, β-Ala, Glu or Aib;     -   A²³ is Gln, Asp, Asn or Glu;     -   A²⁴ is Ala, Aib, Val, Abu, Tle or Acc;     -   A²⁵ is Ala, Aib, Val, Abu, Tle, Acc, Lys, Arg, hArg, Orn,         HN—CH((CH₂)_(n)—N(R¹⁰R¹¹))—C(O) or HN—CH((CH₂)_(e)—X³)—C(O);     -   A²⁶ is Lys, Arg, hArg, Orn, HN—CH((CH₂)_(n)—N(R¹⁰R¹¹))—C(O) or         HN—CH((CH₂)_(e)—X³)—C(O);     -   A²⁷ is Glu Asp, Leu, Aib or Lys;     -   A²⁸ is Phe, Pal, β-Nal, X¹-Phe, Aic, Acc, Aib, Cha or Trp;     -   A²⁹ is Ile, Acc, Aib, Leu, Nle, Cha, Tle, Val, Abu, Ala or Phe;     -   A³⁰ is Ala, Aib or Acc;     -   A³¹ is Trp, β-Nal, 3-Pal, 4-Pal, Phe, Acc, Aib or Cha;     -   A³² is Leu, Acc, Aib, Nle, Ile, Cha, Tle, Phe, X¹-Phe or Ala;     -   A³³ is Val, Acc, Aib, Leu, Ile, Tle, Nle, Cha, Ala, Phe, Abu,         Lys or X¹-Phe;     -   A³⁴ is Lys, Arg, hArg, Orn, HN—CH((CH₂)_(n)—N(R¹⁰R¹¹))—C(O) or         HN—CH((CH₂)_(e)—X³)—C(O);     -   A³⁵ is Gly, β-Ala, D-Ala, Gaba, Ava, HN—(CH₂)_(m)—C(O), Aib, Acc         or a D-amino acid;     -   A³⁶ is L- or D-Arg, D- or L-Lys, D- or L-hArg, D- or L-Orn,         HN—CH((CH₂)_(n)—N(R¹⁰R¹¹))—C(O), HN—CH((CH₂)_(e)—X³)—C(O) or         deleted;     -   A³⁷ is Gly, β-Ala, Gaba, Ava, Aib, Acc, Ado, Arg, Asp, Aun, Aec,         HN—(CH₂)_(m)—C(O), HN—CH((CH₂)_(n)—N(R¹⁰R¹¹))—C(O), a D-amino         acid, or deleted;     -   A³⁸ is D- or L-Lys, D- or L-Arg, D- or L-hArg, D- or L-Orn,         HN—CH((CH₂)_(n)—N(R¹⁰R¹¹))—C(O), HN—CH((CH₂)_(e)—X³)—C(O) Ava,         Ado, Aec or deleted;     -   A³⁹ is D- or L-Lys, D- or L-Arg,         HN—CH((CH₂)_(n)—N(R¹⁰R¹¹))—C(O), Ava, Ado, or Aec; X¹ for each         occurrence is independently selected from the group consisting         of (C₁-C₆)alkyl, OH and halo;     -   R¹ is OH, NH₂, (C₁-C₃₀)alkoxy, or NH—X²—CH₂-Z⁰, wherein X² is a         (C₁-C₁₂)hydrocarbon moiety, and Z⁰ is H, OH, CO₂H or CONH₂;         or —C(O)—NHR¹², wherein X⁴ is, independently for each         occurrence, —C(O)—, —NH—C(O)— or —CH₂—, and wherein f is,         independently for each occurrence, an integer from 1 to 29         inclusive;     -   each of R² and R³ is independently selected from the group         consisting of H, (C₁-C₃₀)alkyl, (C₂-C₃₀)alkenyl,         phenyl(C₁-C₃₀)alkyl, naphthyl(C₁-C₃₀)alkyl,         hydroxy(C₁-C₃₀)alkyl, hydroxy(C₂-C₃₀)alkenyl,         hydroxyphenyl(C₁-C₃₀)alkyl, and hydroxynaphthyl(C₁-C₃₀)alkyl; or         one of R² and R³ is         (C₁-C₃₀)acyl, (C₁-C₃₀)alkylsulfonyl, C(O)X⁵,         wherein Y is H, OH or NH₂; r is 0 to 4; q is 0 to 4;     -   and X⁵ is (C₁-C₃₀)alkyl, (C₂-C₃₀)alkenyl, phenyl(C₁-C₃₀)alkyl,         naphthyl(C₁-C₃₀)alkyl, hydroxy(C₁-C₃₀)alkyl,         hydroxy(C₂-C₃₀)alkenyl, hydroxyphenyl(C₁-C₃₀)alkyl or         hydroxynaphthyl(C₁-C₃₀)alkyl;     -   e is, independently for each occurrence, an integer from 1 to 4         inclusive;     -   m is, independently for each occurrence, an integer from 5 to 24         inclusive;     -   n is, independently for each occurrence, an integer from 1 to 5,         inclusive;     -   each of R¹⁰ and R¹¹ is, independently for each occurrence, H,         (C₁-C₃₀)alkyl, (C₁-C₃₀)acyl, (C₁-C₃₀)alkylsulfonyl,         —C((NH)(NH₂)) or         and     -   R¹² and R¹³ each is, independently for each occurrence,         (C₁-C₃₀)alkyl;     -   provided that:     -   when A⁷ is Ura, Paa or Pta, then R² and R³ are deleted;     -   when R¹⁰ is (C₁-C₃₀)acyl, _(C₁-C₃₀)alkylsulfonyl, —C((NH)(NH₂))         or         then R¹¹ is H or (C₁-C₃₀)alkyl;     -   (i) at least one amino acid of a compound of formula (I) is not         the same as the native sequence of hGLP-1(7-36, -37 or -38)NH₂         or hGLP-1(7-36, -37 or -38)OH;     -   (ii) a compound of formula (I) is not an analogue of         hGLP-1(7-36, -37 or -38)NH₂ or hGLP-1(7-36, -37 or -38)OH         wherein a single position has been substituted by Ala;     -   (iii) a compound of formula (I) is not (Arg^(26,34),         Lys³⁸)hGLP-1(7-38)-E, (Lys²⁶(N_(ε)-alkanoyl))hGLP-1(7-36, -37 or         -38)-E, (Lys³⁴(N_(ε)-alkanoyl))hGLP-1(7-36, -37 or -38)-E,         (Lys^(26,34)-bis(N_(ε)-alkanoyl))hGLP-1(7-36, -37 or -38)-E,         (Arg²⁶, Lys³⁴(N_(ε)-alkanoyl))hGLP-1(8-36, -37 or -38)-E,         (Arg^(26,34), Lys³⁶(N_(ε)-alkanoyl))hGLP-1(7-36, -37 or -38)-E         or (Arg^(26,34), Lys³⁸(N_(ε)-alkanoyl))hGLP-1(7-38)-E, wherein E         is —OH or —NH₂;     -   (iv) a compound of formula (I) is not Z¹-hGLP-1(7-36, -37 or         -38)-OH, Z¹-hGLP-1(7-36, -37 or -38)-NH₂, wherein Z¹ is selected         from the group consisting of:         -   (a) (Arg²⁶), (Arg³⁴), (Arg^(26,34)), (Lys³⁶), (Arg²⁶,             Lys³⁶), (Arg³⁴, Lys³⁶), (D-Lys³⁶), (Arg³⁶), (D-Arg³⁶),             (Arg^(26,34), Lys³⁶) or (Arg^(26,36), Lys³⁴);         -   (b) (Asp²¹);         -   (c) at least one of (Aib⁸), (D-Ala⁸) and (Asp⁹); and         -   (d) (Tyr⁷), (N-acyl-His⁷), (N-alkyl-His⁷), (N-acyl-D-His⁷)             or (N-alkyl-D-His⁷);     -   (v) a compound of formula (I) is not a combination of any two of         the substitutions listed in groups (a) to (d); and     -   (vi) a compound of formula (I) is not (N-Me-Ala⁸)hGLP-1(8-36 or         -37), (Glu¹⁵)hGLP-1(7-36 or -37), (Asp²¹)hGLP-1(7-36 or -37) or         (Phe³¹)hGLP-1(7-36 or -37)     -   or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing compound is where A¹¹ is Thr; A¹³ is Thr; A¹⁵ is Asp; A¹⁷ is Ser; A¹⁸ is Ser or Lys; A²¹ is Glu; A²³ is Gln or Glu; A²⁷ is Glu, Leu, Aib or Lys; and A³¹ is Trp, Phe or β-Nal; or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing group of compounds is where A⁹ is Glu, N-Me-Glu or N-Me-Asp; A¹² is Phe, Acc, β-Nal or Aic; A¹⁶ is Val, Acc or Aib; A¹⁹ is Tyr or β-Nal; A²⁰ is Leu, Acc or Cha; A²⁴ is Ala, Aib or Acc; A²⁵ is Ala, Aib, Acc, Lys, Arg, hArg, Orn, HN—CH((CH₂)_(n)—N(R¹⁰R¹¹))—C(O) or HN—CH((CH₂)_(e)—X³)—C(O); A²⁸ is Phe or β-Nal; A²⁹ is Ile or Acc; A³⁰ is Ala or Aib; A³² is Leu, Acc or Cha; and A³³ is Val, Lys or Acc; or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing group of compounds is where A⁸ is Ala, D-Ala, Aib, A6c, A5c, N-Me-Ala, N-Me-D-Ala or N-Me-Gly; A¹⁰ is Gly; A¹² is Phe, β-Nal, A6c or A5c; A¹⁶ is Val, A6c or A5c; A²⁰ is A6c, A5c or Cha; A²² is Gly, β-Ala, Glu or Aib; A²⁴ is Ala or Aib; A²⁹ is Ile, A6c or A5c; A³² is Leu, A6c, A5c or Cha; A³³ is Val, Lys, A6c or A5c; A³⁵ is Aib, β-Ala, Ado, A6c, A5c, D-Arg or Gly; and A³⁷ is Gly, Aib, β-Ala, Ado, D-Ala Ava, Asp, Aun, D-Asp, D-Arg, Aec, HN—CH((CH₂)_(n)—N(R¹⁰R¹¹))—C(O) or deleted; or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing group of compounds is where X⁴ for each occurrence is —C(O)—; and R¹ is OH or NH₂; or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing group of compounds or a pharmaceutically acceptable salt thereof is where R² is H and R³ is (C₁-C₃₀)alkyl, (C₂-C₃₀)alkenyl, (C₁-C₃₀)acyl, (C₁-C₃₀)alkylsulfonyl,

A preferred compound of the formula (I) is where A⁸ is Ala, D-Ala, Aib, A6c, A5c, N-Me-Ala, N-Me-D-Ala or N-Me-Gly; A¹⁰ is Gly; A¹² is Phe, β-Nal A6c or A5c; A¹⁶ is Val, A6c or A5c; A²⁰ is Leu, A6c, A5c or Cha; A²² is Gly, β-Ala, Glu or Aib; A²⁴ is Ala or Aib; A²⁹ is Ile, A6c or A5c; A³² is Leu, A6c, A5c or Cha; A³³ is Val, Lys, A6c or A5c; A³⁵ is Aib, β-Ala, Ado, A6c, A5c D-Arg or Gly; and A³⁷ is Gly, Aib, β-Ala, Ado, D-Ala, Ava, Asp, Aun, D-Asp, D-Arg, Aec, HN—CH((CH₂)_(n)—N(R¹⁰R¹¹))—C(O) or deleted; X⁴ for each occurrence is —C(O)—; e for each occurrence is independently 1 or 2; R¹ is OH or NH₂; R¹⁰ is (C₁-C₃₀)acyl, (C₁-C₃₀)alkylsulfonyl or

and R¹¹ is H; or a pharmaceutically acceptable salt thereof.

More preferred of the immediately foregoing compounds is where R¹⁰ is (C₄-C₂₀)acyl, (C₄-C₂₀)alkylsulfonyl or

or a pharmaceutically acceptable salt thereof.

A more preferred compound of formula (I) is where said compound is of the formula: (Aib^(8,35))hGLP-1(7-36)NH₂, ((N_(α)-HEPES-His)⁷, Aib^(8,35))hGLP-1(7-36)NH₂, ((N_(α)-HEPA-His)⁷, Aib^(8,35))hGLP-1(7-36)NH₂, (Aib⁸, β-Ala³⁵)hGLP-1(7-36)NH₂, (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-tetradecanoyl))hGLP-1(7-36)NH₂, (Aib^(8,35), Arg²⁶, Lys³⁴(N_(ε)-tetradecanoyl))hGLP-1(7-36)NH₂, (Aib^(8,35,37), Arg^(26,34), Lys³⁸(N_(ε)-tetradecanoyl))hGLP-1(7-38)NH₂, (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-decanoyl))hGLP-1(7-36)NH₂, (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-dodecanesulfonyl))hGLP-1(7-36)NH₂, (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂, (Aib^(8,35), Arg^(26,34), Asp³⁶(1-(4-tetradecyl-piperazine)))hGLP-1(7-36)NH₂, (Aib^(8,35), Arg^(26,34), Asp³⁶(1-tetradecylamino))hGLP-1(7-36)NH₂, (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-tetradecanoyl),β-Ala³⁷)hGLP-1(7-37)-OH or (Aib^(8,35), Arg^(28,34), Lys³⁶(N_(ε)-tetradecanoyl))hGLP-1(7-36)-OH, or a pharmaceutically acceptable salt thereof.

More preferred of the immediately foregoing group of compounds is a compound of the formula: (Aib^(8,35))hGLP-1(7-36)NH₂, (Aib⁸, β-Ala³⁵)hGLP-1(7-36)NH₂, (Aib^(8,35), Arg²⁶, Lys³⁴(N_(ε)-tetradecanoyl))hGLP-1(7-36)NH₂, (Aib^(8,35,37), Arg^(26,34), Lys³⁸(N_(ε)-tetradecanoyl))hGLP-1 (7-38)NH₂, (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-decanoyl))hGLP-1(7-36)NH₂, or (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-tetradecanoyl),β-Ala³⁷)hGLP-1(7-37) —OH, or a pharmaceutically acceptable salt thereof.

Another more preferred compound of formula (I) is where said compound is of the formula: (Aib^(8,35), A6c³²)hGLP-1(7-36)NH₂; (Aib^(8,35), Glu²³)hGLP-1(7-36)NH₂; (Aib^(8,24,35))hGLP-1(7-36)NH₂; (Aib^(8,35), Glu²³, A6C³²)hGLP-1(7-36)NH₂; (Aib⁸, Glu²³, β-Ala³⁵)hGLP-1(7-36)NH₂; (Aib^(8,35), Arg^(26,34))hGLP-1(7-36)NH₂; (Aib^(8,35), Arg^(26,34), Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂; (Aib^(8,35), Arg^(26,34), Lys³⁶(N^(ε)-decanoyl))hGLP-1(7-36)OH; (Aib^(8,35), Lys²⁵, Arg^(26,34), Lys³⁶(N^(ε)-decanoyl))hGLP-1(7-36)OH; (Aib⁸, Arg^(26,34), β-Ala³⁵, Lys³⁶(N^(ε)-Aec-decanoyl))hGLP-1(7-36)NH₂; (Aib^(8,35), Arg^(26,34), Ava³⁷, Ado³⁸)hGLP-1(7-38)NH₂; (Aib^(8,35), Arg^(26,34), Asp³⁷, Ava³⁸, Ado³⁹)hGLP-1(7-39)NH₂; (Aib^(8,35), Arg^(26,34), Aun³⁷)hGLP-1(7-37)NH₂; (Aib^(8,17,35),)hGLP-1(7-36)NH₂; (Aib⁸, Arg^(26,34), β-Ala³⁵, D-Asp³⁷, Ava³⁸, Aun³⁹)hGLP-1(7-39)NH₂; (Gly⁸, β-Ala³⁵)hGLP-1(7-36)NH₂; (Ser⁸, β-Ala³⁵)hGLP-1(7-36)NH₂; (Aib⁸, Glu^(22,23), β-Ala³⁵)hGLP-1(7-36)NH₂; (Gly⁸, Aib³⁵)hGLP-1(7-36)NH₂; (Aib⁸, Lys¹⁸, β-Ala³⁵)hGLP-1(7-36)NH₂; (Aib⁸, Leu²⁷, β-Ala³⁵)hGLP-1(7-36)NH₂; (Aib⁸, Lys³³, β-Ala³⁵)hGLP-1(7-36)NH₂; (Aib⁸, Lys¹⁸, Leu²⁷, β-Ala³⁵)hGLP-1(7-36)NH₂; (Aib⁸, D-Arg³⁶)hGLP-1(7-36)NH₂; (Aib⁸, β-Ala³⁵, D-Arg³⁷)hGLP-1(7-37)NH₂; (Aib^(8,27), β-Ala³⁵)hGLP-1(7-36)NH₂; (Aib^(8,27), β-Ala^(35,37), Arg³⁸)hGLP-1(7-38)NH₂; (Aib^(8,27), β-Ala^(35,37), Arg^(38,39))hGLP-1(7-39)NH₂; (Aib⁸, Lys^(18,27), β-Ala³⁵)hGLP-1(7-36)NH₂; (Aib⁸, Lys²⁷, β-Ala³⁵)hGLP-1(7-36)NH₂; (Aib⁸, β-Ala³⁵, Arg³⁸)hGLP-1(7-38)NH₂; (Aib⁸, Arg^(26,34), β-Ala³⁵,)hGLP-1(7-36)NH₂; (Aib⁸, D-Arg³⁵)hGLP-1(7-36)NH₂; (Aib⁸, β-Ala³⁵, Arg³⁷)hGLP-1(7-37)NH₂; (Aib⁸, Phe³¹, β-Ala³⁵)hGLP-1(7-36)NH₂; (Aib^(8,35), Phe³¹)hGLP-1(7-36)NH₂; (Aib^(8,35), Nal³¹ )hGLP-1(7-36)NH₂; (Aib^(8,35), Nal^(28,31))hGLP-1(7-36)NH₂; (Aib^(8,35), Arg^(26,34), Nal³¹ )hGLP-1(7-36)NH₂; (Aib^(8,35), Arg^(26,34), Phe³¹)hGLP-1(7-36)NH₂; (Aib^(8,35), Nal^(19,31))hGLP-1(7-36)NH₂; (Aib^(8,35), Nal^(12,31))hGLP-1(7-36)NH₂; (Aib^(8,35), Lys³⁶(N^(ε)-decanoyl))hGLP-1(7-36)NH₂; (Aib^(8,35), Arg³⁴, Lys²⁶(N^(ε)-decanoyl))hGLP-1(7-36)NH₂; (Aib^(8,35), Arg^(26,34), Lys³⁶(N^(ε)-dodecanoyl))hGLP-1(7-36)NH₂; (Aib⁸, B-Ala³⁵, Ser³⁷(O-decanoyl))hGLP1(7-37)-NH₂; (Aib^(8,27), β-Ala^(35,37), Arg³⁸, Lys³⁹(N^(ε)-octanoyl))hGLP-1(7-39)NH₂; (Aib⁸, Arg^(26,34), β-Ala³⁵, Lys³⁷(N^(ε)-octanoyl))hGLP-1(7-37)NH₂; (Aib⁸, Arg^(26,34), β-Ala³⁵, Lys³⁷(N^(ε)-decanoyl))hGLP-1(7-37)NH₂; or (Aib⁸, Arg^(26,34), β-Ala³⁵, Lys³⁷(N^(ε)-tetradecanoyl))hGLP-1(7-37)NH₂; or a pharmaceutically acceptable salt thereof.

Another more preferred compound of formula (I) is each of the compounds that are specifically enumerated hereinbelow in the Examples section of the present disclosure, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) as defined hereinabove or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

In yet another aspect, the present invention provides a method of eliciting an agonist effect from a GLP-1 receptor in a subject in need thereof which comprises administering to said subject an effective amount of a compound of formula (I) as defined hereinabove or a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides a method of treating a disease selected from the group consisting of Type I diabetes, Type II diabetes, obesity, glucagonomas, secretory disorders of the airway, metabolic disorder, arthritis, osteoporosis, central nervous system disease, restenosis, neurodegenerative disease, renal failure, congestive heart failure, nephrotic syndrome, cirrhosis, pulmonary edema, hypertension, and disorders wherein the reduction of food intake is desired, in a subject in need thereof which comprises administering to said subject an effective amount of a compound of formula (I) as defined hereinabove or a pharmaceutically acceptable salt thereof. A preferred method of the immediately foregoing method is where the disease being treated is Type I diabetes or Type II diabetes.

With the exception of the N-terminal amino acid, all abbreviations (e.g. Ala) of amino acids in this disclosure stand for the structure of —NH—CH(R)—CO—, wherein R is the side chain of an amino acid (e.g., CH₃ for Ala). For the N-terminal amino acid, the abbreviation stands for the structure of (R²R³)—N—CH(R)—CO—, wherein R is a side chain of an amino acid and R² and R³ are as defined above, except when A⁷ is Ura, Paa or Pta, in which case R² and R³ are not present since Ura, Paa and Pta are considered here as des-amino amino acids. Amp, β-Nal, Nle, Cha, 3-Pal, 4-Pal and Aib are the abbreviations of the following α-amino acids: 4-amino-phenylalanine, β-(2-naphthyl)alanine, norleucine, cyclohexylalanine, β-(3-pyridinyl)alanine, β-(4-pyridinyl)alanine and α-aminoisobutyric acid, respectively. Other amino acid definitions are: Ura is urocanic acid; Pta is (4-pyridylthio) acetic acid; Paa is trans-3-(3-pyridyl) acrylic acid; Tma-His is N,N-tetramethylamidino-histidine; N-Me-Ala is N-methyl-alanine; N-Me-Gly is N-methyl-glycine; N-Me-Glu is N-methyl-glutamic acid; Tle is tert-butylglycine; Abu is α-aminobutyric acid; Tba is tert-butylalanine; Orn is ornithine; Aib is α-aminoisobutyric acid; β-Ala is β-alanine; Gaba is γ-aminobutyric acid; Ava is 5-aminovaleric acid; Ado is 12-aminododecanoic acid, Aic is 2-aminoindane-2-carboxylic acid; Aun is 11-aminoundecanoic acid; and Aec is 4-(2-aminoethyl)-1-carboxymethyl-piperazine, represented by the structure:

What is meant by Acc is an amino acid selected from the group of 1-amino-1-cyclopropanecarboxylic acid (A3c); 1-amino-1-cyclobutanecarboxylic acid (A4c); 1-amino-1-cyclopentanecarboxylic acid (A5c); 1-amino-1-cyclohexanecarboxylic acid (A6c); 1-amino-1-cycloheptanecarboxylic acid (A7c); 1-amino-1-cyclooctanecarboxylic acid (A8c); and 1-amino-1-cyclononanecarboxylic acid (A9c). In the above formula, hydroxyalkyl, hydroxyphenylalkyl, and hydroxynaphthylalkyl may contain 1-4 hydroxy substituents. COX⁵ stands for —C═O.X⁵. Examples of —C═O.X⁵ include, but are not limited to, acetyl and phenylpropionyl.

What is meant by Lys(N_(ε)-alkanoyl) is represented by the following structure:

What is meant by Lys(N_(ε)-alkylsulfonyl) is represented by the following structure:

What is meant by Lys(N_(ε)-(2-(4-alkyl-1-piperazine)-acetyl)) is represented by the following structure:

What is meant by Asp(1-(4-alkyl-piperazine)) is represented by the following structure:

What is meant by Asp(1-alkylamino) is represented by the following structure:

What is meant by Lys(N_(ε)-Aec-alkanoyl) is represented by the structure:

The variable n in the foregoing structures is 1-30. What is meant by Lys (Nε-ace-alkanoyl) is represented by the structure:

The full names for other abbreviations used herein are as follows: Boc for t-butyloxycarbonyl, HF for hydrogen fluoride, Fm for formyl, Xan for xanthyl, Bzl for benzyl, Tos for tosyl, DNP for 2,4-dinitrophenyl, DMF for dimethylformamide, DCM for dichloromethane, HBTU for 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate, DIEA for diisopropylethylamine, HOAc for acetic acid, TFA for trifluoroacetic acid, 2ClZ for 2-chlorobenzyloxycarbonyl, 2BrZ for 2-bromobenzyloxycarbonyl, OcHex for O-cyclohexyl, Fmoc for 9-fluorenylmethoxycarbonyl, HOBt for N-hydroxybenzotriazole and PAM resin for 4-hydroxymethylphenylacetamidomethyl resin.

The term “halo” encompasses fluoro, chloro, bromo and iodo.

The term “(C₁-C₃₀)hydrocarbon moiety” encompasses alkyl, alkenyl and alkynyl, and in the case of alkenyl and alkynyl there are C₂-C₃₀.

A peptide of this invention is also denoted herein by another format, e.g., (A5c⁸)hGLP-1(7-36)NH₂, with the substituted amino acids from the natural sequence placed between the first set of parentheses (e.g., A5c⁸ for Ala⁸ in hGLP-1). The abbreviation GLP-1 means glucagon-like peptide-1; hGLP-1 means human glucagon-like peptide-1. The numbers between the parentheses refer to the number of amino acids present in the peptide (e.g., hGLP-1(7-36) is amino acids 7 through 36 of the peptide sequence for human GLP-1). The sequence for hGLP-1(7-37) is listed in Mojsov, S., Int. J. Peptide Protein Res,. 40, 1992, pp. 333-342. The designation “NH₂” in hGLP-1(7-36)NH₂ indicates that the C-terminus of the peptide is amidated. hGLP-1(7-36) means that the C-terminus is the free acid. In hGLP-1(7-38), residues in positions 37 and 38 are Gly and Arg, respectively.

DETAILED DESCRIPTION

The peptides of this invention can be prepared by standard solid phase peptide synthesis. See, e.g., Stewart, J. M., et al., Solid Phase Synthesis (Pierce Chemical Co., 2d ed. 1984). The substituents R² and R3 of the above generic formula may be attached to the free amine of the N-terminal amino acid by standard methods known in the art. For example, alkyl groups, e.g., (C₁-C₃₀)alkyl, may be attached using reductive alkylation. Hydroxyalkyl groups, e.g., (C₁-C₃₀)hydroxyalkyl, may also be attached using reductive alkylation wherein the free hydroxy group is protected with a t-butyl ester. Acyl groups, e.g., COE¹, may be attached by coupling the free acid, e.g., E¹COOH, to the free amine of the N-terminal amino acid by mixing the completed resin with 3 molar equivalents of both the free acid and diisopropylcarbodiimide in methylene chloride for one hour. If the free acid contains a free hydroxy group, e.g., p-hydroxyphenylpropionic acid, then the coupling should be performed with an additional 3 molar equivalents of HOBT.

When R¹ is NH—X²—CH₂—CONH₂, (i.e., Z⁰=CONH₂), the synthesis of the peptide starts with BocHN—X²—CH₂—COOH which is coupled to the MBHA resin. If R¹ is NH—X²—CH₂—COOH, (i.e., Z⁰=COOH) the synthesis of the peptide starts with Boc-HN—X²—CH₂—COOH which is coupled to PAM resin. For this particular step, 4 molar equivalents of Boc-HN—X²—COOH, HBTU and HOBt and 10 molar equivalents of DIEA are used. The coupling time is about 8 hours.

The protected amino acid 1-(N-tert-butoxycarbonyl-amino)-1-cyclohexanecarboxylic acid (Boc-A6c-OH) was synthesized as follows. 19.1 g (0.133 mol) of 1-amino-1-cyclohexanecarboxylic acid (Acros Organics, Fisher Scientific, Pittsburgh, Pa.) was dissolved in 200 ml of dioxane and 100 ml of water. To it was added 67 ml of 2N NaOH. The solution was cooled in an ice-water bath. 32.0 g (0.147 mol) of di-tert-butyl-dicarbonate was added to this solution. The reaction mixture was stirred overnight at room temperature. Dioxane was then removed under reduced pressure. 200 ml of ethyl acetate was added to the remaining aqueous solution. The mixture was cooled in an ice-water bath. The pH of the aqueous layer was adjusted to about 3 by adding 4N HCl. The organic layer was separated. The aqueous layer was extracted with ethyl acetate (1×100 ml). The two organic layers were combined and washed with water (2×150 ml), dried over anhydrous MgSO₄, filtered, and concentrated to dryness under reduced pressure. The residue was recrystallized in ethyl acetate/hexanes. 9.2 g of the pure product was obtained. 29% yield.

Boc-A5c-OH was synthesized in an analogous manner to that of Boc-A6c-OH. Other protected Acc amino acids can be prepared in an analogous manner by a person of ordinary skill in the art as enabled by the teachings herein.

In the synthesis of a GLP-1 analogue of this invention containing A5c, A6c and/or Aib, the coupling time is 2 hrs. for these residues and the residue immediately following them. For the synthesis of (Tma-His⁷)hGLP-1(7-36)NH₂, HBTU (2 mmol) and DIEA (1.0 ml) in 4 ml DMF are used to react with the N-terminal free amine of the peptide-resin in the last coupling reaction; the coupling time is about 2 hours.

The substituents R² and R³ of the above generic formula can be attached to the free amine of the N-terminal amino acid by standard methods known in the art. For example, alkyl groups, e.g., (C₁-C₃₀)alkyl, can be attached using reductive alkylation. Hydroxyalkyl groups, e.g., (C₁-C₃₀)hydroxyalkyl, can also be attached using reductive alkylation wherein the free hydroxy group is protected with a t-butyl ester. Acyl groups, e.g., COX¹, can be attached by coupling the free acid, e.g., X¹COOH, to the free amine of the N-terminal amino acid by mixing the completed resin with 3 molar equivalents of both the free acid and diisopropylcarbodiimide in methylene chloride for about one hour. If the free acid contains a free hydroxy group, e.g., p-hydroxyphenylpropionic acid, then the coupling should be performed with an additional 3 molar equivalents of HOBT.

A compound of the present invention can be tested for activity as a GLP-1 binding compound according to the following procedure.

Cell Culture:

RIN 5F rat insulinoma cells (ATCC-# CRL-2058, American Type Culture Collection, Manassas, Va.), expressing the GLP-1 receptor, were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum, and maintained at about 37° C. in a humidifed atmosphere of 5% CO₂/95% air.

Radioligand Binding:

Membranes were prepared for radioligand binding studies by homogenization of the RIN cells in 20 ml of ice-cold 50 mM Tris-HCl with a Brinkman Polytron (Westbury, N.Y.) (setting 6, 15 sec). The homogenates were washed twice by centrifugation (39,000 g/10 min), and the final pellets were resuspended in 50 mM Tris-HCl, containing 2.5 mM MgCl₂, 0.1 mg/ml bacitracin (Sigma Chemical, St. Louis, Mo.), and 0.1% BSA. For assay, aliquots (0.4 ml) were incubated with 0.05 nM (¹²⁵I)GLP-1(7-36) (˜2200 Ci/mmol, New England Nuclear, Boston, Mass.), with and without 0.05 ml of unlabeled competing test peptides. After a 100 min incubation (25° C.), the bound (¹²⁵I)GLP-1(7-36) was separated from the free by rapid filtration through GF/C filters (Brandel, Gaithersburg, Md.), which had been previously soaked in 0.5% polyethyleneimine. The filters were then washed three times with 5 ml aliquots of ice-cold 50 mM Tris-HCl, and the bound radioactivity trapped on the filters was counted by gamma spectrometry (Wallac L K B, Gaithersburg, Md.). Specific binding was defined as the total (¹²⁵I)GLP-1(7-36) bound minus that bound in the presence of 1000 nM GLP1(7-36) (Bachem, Torrence, Calif.).

The peptides of this invention can be provided in the form of pharmaceutically acceptable salts. Examples of such salts include, but are not limited to, those formed with organic acids (e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, methanesulfonic, toluenesulfonic, or pamoic acid), inorganic acids (e.g., hydrochloric acid, sulfuric acid, or phosphoric acid), and polymeric acids (e.g., tannic acid, carboxymethyl cellulose, polylactic, polyglycolic, or copolymers of polylactic-glycolic acids). A typical method of making a salt of a peptide of the present invention is well known in the art and can be accomplished by standard methods of salt exchange. Accordingly, the TFA salt of a peptide of the present invention (the TFA salt results from the purification of the peptide by using preparative HPLC, eluting with TFA containing buffer solutions) can be converted into another salt, such as an acetate salt by dissolving the peptide in a small amount of 0.25 N acetic acid aqueous solution. The resulting solution is applied to a semi-prep HPLC column (Zorbax, 300 SB, C-8). The column is eluted with (1) 0.1N ammonium acetate aqueous solution for 0.5 hrs., (2) 0.25N acetic acid aqueous solution for 0.5 hrs. and (3) a linear gradient (20% to 100% of solution B over 30 min.) at a flow rate of 4 ml/min (solution A is 0.25N acetic acid aqueous solution; solution B is 0.25N acetic acid in acetonitrile/water, 80:20). The fractions containing the peptide are collected and lyophilized to dryness.

As is well known to those skilled in the art, the known and potential uses of GLP-1 is varied and multitudinous (See, Todd, J. F., et al., Clinical Science, 1998, 95, pp. 325-329; and Todd, J. F. et al., European Journal of Clinical Investigation, 1997, 27, pp.533-536). Thus, the administration of the compounds of this invention for purposes of eliciting an agonist effect can have the same effects and uses as GLP-1 itself. These varied uses of GLP-1 may be summarized as follows, treatment of: Type I diabetes, Type II diabetes, obesity, glucagonomas, secretory disorders of the airway, metabolic disorder, arthritis, osteoporosis, central nervous system diseases, restenosis, neurodegenerative diseases, renal failure, congestive heart failure, nephrotic syndrome, cirrhosis, pulmonary edema, hypertension, and disorders wherein the reduction of food intake is desired. GLP-1 analogues of the present invention that elicit an antagonist effect from a subject can be used for treating the following: hypoglycemia and malabsorption syndrome associated with gastroectomy or small bowel resection.

Accordingly, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of formula (I) in association with a pharmaceutically acceptable carrier.

The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. In general, an effective dosage for the activities of this invention is in the range of 1×10⁻⁷ to 200 mg/kg/day, preferably 1×10⁻⁴ to 100 mg/kg/day, which can be administered as a single dose or divided into multiple doses.

The compounds of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.

Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.

Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as coca butter or a suppository wax.

Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.

Further, a compound of this invention can be administered in a sustained release composition such as those described in the following patents and patent applications. U.S. Pat. No. 5,672,659 teaches sustained release compositions comprising a bioactive agent and a polyester. U.S. Pat. No. 5,595,760 teaches sustained release compositions comprising a bioactive agent in a gelable form. U.S. application Ser. No. 08/929,363 filed Sep. 9, 1997, teaches polymeric sustained release compositions comprising a bioactive agent and chitosan. U.S. application Ser. No. 08/740,778 filed Nov. 1, 1996, teaches sustained release compositions comprising a bioactive agent and cyclodextrin. U.S. application Ser. No. 09/015,394 filed Jan. 29, 1998, teaches absorbable sustained release compositions of a bioactive agent. U.S. application Ser. No. 09/121,653 filed Jul. 23, 1998, teaches a process for making microparticles comprising a therapeutic agent such as a peptide in an oil-in-water process. U.S. application Ser. No. 09/131,472 filed Aug. 10, 1998, teaches complexes comprising a therapeutic agent such as a peptide and a phosphorylated polymer. U.S. application Ser. No. 09/184,413 filed Nov. 2, 1998, teaches complexes comprising a therapeutic agent such as a peptide and a polymer bearing a non-polymerizable lactone. The teachings of the foregoing patents and applications are incorporated herein by reference.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Also, all publications, patent applications, patents and other references mentioned herein are incorporated by reference.

The following examples describe synthetic methods for making a peptide of this invention, which methods are well-known to those skilled in the art. Other methods are also known to those skilled in the art. The examples are provided for the purpose of illustration and is not meant to limit the scope of the present invention in any manner.

Boc-βAla-OH, Boc-D-Arg(Tos)-OH and Boc-D-Asp(OcHex) were purchased from Nova Biochem, San Diego, Calif. Boc-Aun-OH was purchased from Bachem, King of Prussia, Pa. Boc-Ava-OH and Boc-Ado-OH were purchased from Chem-Impex International, Wood Dale, Ill. Boc-Nal-OH was purchased from Synthetech, Inc. Albany, Oreg.

EXAMPLE 1 (Aib^(8,35))hGLP-1(7-36)NH₂

The title peptide was synthesized on an Applied Biosystems (Foster City, Calif.) model 430A peptide synthesizer which was modified to do accelerated Boc-chemistry solid phase peptide synthesis. See Schnolzer, et al., Int. J. Peptide Protein Res., 90:180 (1992). 4-methylbenzhydrylamine (MBHA) resin (Peninsula, Belmont, Calif.) with the substitution of 0.91 mmol/g was used. The Boc amino acids (Bachem, Calif., Torrance, Calif.; Nova Biochem., LaJolla, Calif.) were used with the following side chain protection: Boc-Ala-OH, Boc-Arg(Tos)-OH, Boc-Asp(OcHex)-OH, Boc-Tyr(2BrZ)-OH, Boc-His(DNP)-OH, Boc-Val-OH, Boc-Leu-OH, Boc-Gly-OH, Boc-Gln-OH, Boc-Ile-OH, Boc-Lys(2ClZ)-OH, Boc-Thr(Bzl)-OH, Boc-Ser(Bzl)-OH, Boc-Phe-OH, Boc-Aib-OH, Boc-Glu(OcHex)-OH and Boc-Trp(Fm)—OH. The synthesis was carried out on a 0.20 mmol scale. The Boc groups were removed by treatment with 100% TFA for 2×1 min. Boc amino acids (2.5 mmol) were pre-activated with HBTU (2.0 mmol) and DIEA (1.0 mL) in 4 mL of DMF and were coupled without prior neutralization of the peptide-resin TFA salt. Coupling times were 5 min. except for the Boc-Aib-OH residues and the following residues, Boc-Lys(2ClZ)-OH and Boc-His(DNP)-OH wherein the coupling times were 2 hours.

At the end of the assembly of the peptide chain, the resin was treated with a solution of 20% mercaptoethanol/10% DIEA in DMF for 2×30 min. to remove the DNP group on the His side chain. The N-terminal Boc group was then removed by treatment with 100% TFA for 2×2 min. After neutralization of the peptide-resin with 10% DIEA in DMF (1×1 min), the formyl group on the side chain of Trp was removed by treatment with a solution of 15% ethanolamine/15% water/70% DMF for 2×30 min. The peptide-resin was washed with DMF and DCM and dried under reduced pressure. The final cleavage was done by stirring the peptide-resin in 10 mL of HF containing 1 mL of anisole and dithiothreitol (24 mg) at 0° C. for 75 min. HF was removed by a flow of nitrogen. The residue was washed with ether (6×10 mL) and extracted with 4N HOAc (6×10 mL).

The peptide mixture in the aqueous extract was purified on reverse-phase preparative high pressure liquid chromatography (HPLC) using a reverse phase VYDAC®) C₁₈ column (Nest Group, Southborough, Mass.). The column was eluted with a linear gradient (20% to 50% of solution B over 105 min.) at a flow rate of 10 mL/min (Solution A =water containing 0.1% TFA; Solution B=acetonitrile containing 0.1% of TFA). Fractions were collected and checked on analytical HPLC. Those containing pure product were combined and lyophilized to dryness. 135 mg of a white solid was obtained. Purity was 98.6% based on analytical HPLC analysis. Electro-spray mass spectrometer (MS(ES))S analysis gave the molecular weight at 3339.7 (in agreement with the calculated molecular weight of 3339.7).

EXAMPLE 2 ((N_(α)-HEPES-His)⁷, Aib^(8,35))hGLP-1(7-36)NH₂

The title compound (HEPES is (4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid)) can be synthesized as follows: after assembly of the peptide (Aib^(8,35))hGLP-1(7-36)NH₂ on MBHA resin (0.20 mmol) according to the procedure of Example 1, the peptide-resin is treated with 100% TFA (2×2 min.) and washed with DMF and DCM. The resin is then neutralized with 10% DIEA in DMF for 2 min. After washing with DMF and DCM, the resin is treated with 0.23 mmol of 2-chloro-1-ethanesulfonyl chloride and 0.7 mmol of DIEA in DMF for about 1 hour. The resin is washed with DMF and DCM and treated with 1.2 mmol of 2-hydroxyethylpiperazine for about 2 hours. The resin is washed with DMF and DCM and treated with different reagents ((1) 20% mercaptoethanol/10% DIEA in DMF and (2) 15% ethanolamine/15% water/70% DMF) to remove the DNP group on the His side chain and formyl group on the Trp side chain as described above before the final HF cleavage of the peptide from the resin.

EXAMPLE 3 ((N_(α)-HEPA-His)⁷, Aib^(8,35))hGLP-1(7-36)NH₂

The title compound (HEPA is (4-(2-hydroxyethyl)-1-piperazineacetyl)) can be made substantially according to the procedure described in Example 2 for making ((N_(α)-HEPES-His)⁷, Aib^(8,35))hGLP-1(7-36)NH₂ except that 2-bromoacetic anhydride is used in place of 2-chloro-1-ethanesulfonyl chloride.

EXAMPLE 4 (Aib⁸, β-Ala³⁵)hGLP-1(7-36)NH₂

The title compound was synthesized substantially according to the procedure described for Example 1 using the appropriate protected amino acids. MS (ES) gave the molecular weight at 3325.7, calculated MW=3325.8, purity=99%, yield=85 mg.

The synthesis of other compounds of the present invention can be accomplished in substantially the same manner as the procedure described for the synthesis of (Aib^(8,35))hGLP-1(7-36)NH₂ in Example 1 above, but using the appropriate protected amino acids depending on the desired peptide.

EXAMPLE 5 (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-tetradecanoyl))hGLP-1(7-36)NH₂

The Boc amino acids used were the same as those in the synthesis of (Aib^(8,35))hGLP-1(7-36)NH₂ described in Example 1 except that Fmoc-Lys(Boc)-OH was used in this example. The first amino acid residue was coupled to the resin manually on a shaker. 2.5 mmol of Fmoc-Lys(Boc)-OH was dissolved in 4 mL of 0.5N HBTU in DMF. To the solution was added 1 mL of DIEA. The mixture was shaken for about 2 min. To the solution was then added 0.2 mmol of MBHA resin (substitution=0.91 mmol/g). The mixture was shaken for about 1 hr. The resin was washed with DMF and treated with 100% TFA for 2×2 min to remove the Boc protecting group. The resin was washed with DMF. Myristic acid (2.5 mmol) was pre-activated with HBTU (2.0 mmol) and DIEA (1.0 mL) in 4 mL of DMF for 2 min and was coupled to the Fmoc-Lys-resin. The coupling time was about 1 hr. The resin was washed with DMF and treated with 25% piperidine in DMF for 2×20 min to remove the Fmoc protecting group. The resin was washed with DMF and transferred to the reaction vessel of the peptide synthesizer. The following steps synthesis and purification procedures for the peptide were the same as those in the synthesis of (Aib^(8,35))hGLP-1(7-36)NH₂ in Example 1. 43.1 mg of the title compound were obtained as a white solid. Purity was 98% based on analytical HPLC analysis. Electro-spray mass spectrometer analysis gave the molecular weight at 3577.7 in agreement with the calculated molecular weight 3578.7.

EXAMPLES 6-8

Examples 6-8 were synthesized substantially according to the procedure described for Example 5 using the appropriate protected amino acid and the appropriate acid in place of the Myristic acid used in Example 5.

EXAMPLE 6 (Aib^(8,35), Arg²⁶, Lys³⁴(N_(ε)-tetradecanoyl))hGLP-1(7-36)NH₂; Yield=89.6 mg; MS(ES)=3577.2, Calculated MW=3578.7; Purity 96%. EXAMPLE 7 (Aib^(8,35,37), Arg^(26,34), Lys³⁸(N_(ε)-tetradecanoyl))hGLP-1(7-38)NH₂; Yield=63.3 mg; MS(ES)=3818.7; Calculated MW=3819.5; Purity 96%. EXAMPLE 8 (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-decanoyl))hGLP-1(7-36)NH₂; Yield=57.4 mg; MS(ES)=3521.5; Calculated MW=3522.7; Purity 98%; Acid=decanoic acid.

The syntheses of other compounds of the present invention containing Lys(N_(ε)-alkanoyl) residue can be carried out in an analogous manner to the procedure described for Example 5, (Aib^(8,35), Arg^(26,34,) Lys³⁶(N_(ε)-tetradecanoyl))hGLP-1(7-36)NH₂. Fmoc-Lys(Boc)-OH amino acid is used for the residue of Lys(N_(ε)-alkanoyl) in the peptide, while Boc-Lys(2ClZ)-OH amino acid is used for the residue of Lys. If the Lys(N_(ε)-alkanoyl) residue is not at the C-terminus, the peptide fragment immediately prior to the Lys(N_(ε)-alkanoyl) residue is assembled on the resin on the peptide synthesizer first. The appropriate acid corresponding to the desired alkanoyl can be purchased from Aldrich Chemical Co., Inc. Milwaukee, Wis., USA, e.g., octanoic acid, decanoic acid, lauric acid and palmitic acid.

EXAMPLE 9 (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-dodecanesulfonyl))hGLP-1(7-36)NH₂

The Boc amino acids to be used in this synthesis are the same as those used in the synthesis of Example 5. The first amino acid residue is coupled to the resin manually on a shaker. 2.5 mmol of Fmoc-Lys(Boc)-OH is dissolved in 4 mL of 0.5N HBTU in DMF. To the solution is added 1 mL of DIEA. The mixture is shaken for about 2 min. To the solution is then added 0.2 mmol of MBHA resin(substitution=0.91 mmol/g). The mixture is shaken for about 1 hr. The resin is washed with DMF and treated with 100% TFA for 2×2 min to remove the Boc protecting group. The resin is washed with DMF and to it is added 0.25 mmol of 1-dodecanesulfonyl chloride in 4 mL of DMF and 1 mL of DIEA. The mixture is shaken for about 2 hrs. The resin is washed with DMF and treated with 25% piperidine in DMF for 2×20 min to remove the Fmoc protecting group. The resin is washed with DMF and transferred to the reaction vessel of the peptide synthesizer. The synthesis of the rest of the peptide and purification procedures are the same as those described in Example 1.

The syntheses of other compounds of the present invention containing Lys(N_(ε)-alkylsulfonyl) residue can be carried out in an analogous manner to the procedure described in Example 9. Fmoc-Lys(Boc)-OH amino acid is used for the residue of Lys(N_(ε)-alkylsulfonyl) in the peptide, while Boc-Lys(2ClZ)-OH amino acid is used for the residue of Lys. If the Lys(N_(ε)-alkylsulfonyl) residue is not at the C-terminus, the peptide fragment immediately prior to the Lys(N_(ε)-alkylsulfonyl) residue is assembled on the resin on the peptide synthesizer first. The appropriate akylsulfonyl chloride can be obtained from Lancaster Synthesis Inc., Windham, N.H., USA, e.g., 1-octanesulfonyl chloride, 1-decanesulfonyl chloride, 1-dodecanesulfonyl chloride, 1-hexadecanesulfonyl chloride and 1-octadecylsulfonyl chloride.

EXAMPLE 10 (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂

The Boc amino acids to be used for this example are the same as those used in the synthesis of Example 5. The first amino acid residue is coupled to the resin manually on a shaker. 2.5 mmol of Fmoc-Lys(Boc)-OH is dissolved in 4 mL of 0.5N HBTU in DMF. To the solution is added 1 mL of DIEA. The mixture is shaken for about 2 min. To the solution is then added 0.2 mmol of MBHA (substitution=0.91 mmol/g) resin. The mixture is shaken for about 1 hr. The resin is washed with DMF and treated with 100% TFA for 2×2 min to remove the Boc protecting group. The resin is washed with DMF. The 2-bromoacetic acid (2.5 mmol) is pre-activated with HBTU (2.0 mmol) and DIEA (1 mL) in 4 mL of DMF for about 2 min and is added to the resin. The mixture is shaken for about 10 min and washed with DMF. The resin is then treated with 1.2 mmol of piperazine in 4 mL of DMF for about 2 hrs. The resin is washed with DMF and treated with 2 mmol of 1-iodotetradecane for about 4 hrs. After washing with DMF, the resin is treated with 3 mmol of acetic anhydride and 1 mL of DIEA in 4 mL of DMF for about 0.5 hr. The resin is washed with DMF and treated with 25% piperidine in DMF for 2×20 min. The resin is washed with DMF and transferred to the reaction vessel of the peptide synthesizer to continue the synthesis. The remaining synthesis and purification procedures for the peptide are the same as the procedures described for Example 1.

The syntheses of other compounds of the present invention containing Lys(N_(ε)-(2-(4-alkyl-1-piperazine)-acetyl)) residue are carried out in an analogous manner as the procedure described for the synthesis of Example 10. Fmoc-Lys(Boc)-OH amino acid is used for the residue of Lys(N_(ε)-(2-(4-alkyl-1-piperazine)-acetyl)) in the peptide, while Boc-Lys(2ClZ)-OH amino acid is used for the residue of Lys. The corresponding iodoalkane is used for the residue of Lys(N_(ε)-(2-(4-alkyl-1-piperazine)-acetyl)) during the alkylation step. If the Lys(N_(ε)-(2-(4-alkyl-1-piperazine)-acetyl)) residue is not at the C-terminus, the peptide fragment immediately prior to the Lys(N_(ε)-(2-(4-alkyl-1-piperazine)-acetyl)) residue is assembled on the resin on the peptide synthesizer first.

EXAMPLE 11 (Aib^(8,35), Arg^(26,34), Asp³⁶(1 -(4-tetradecyl-piperazine)))hGLP-1(7-36)NH₂

The Boc amino acids to be used in this example are the same as the amino acids used in synthesis of Example 5 except Fmoc-Asp(O-tBu)-OH is used at position 36. The first amino acid residue is coupled to the resin manually on a shaker. 2.5 mmol of Fmoc-Asp(O-tBu)-OH is dissolved in 4 mL of 0.5N HBTU in DMF. To the solution is added 1 mL of DIEA. The mixture is shaken for about 2 min. To the solution is then added 0.2 mmol of MBHA (substitution=0.91 mmol/g) resin. The mixture is shaken for about 1 hr. The resin is washed with DMF and treated with 100% TFA for 2×15 min to remove the tBu protecting group. The resin is washed with DMF and is treated with HBTU (0.6 mmol) and DIEA (1 mL) in 4 mL of DMF for about 15 min. 0.6 mmol of piperazine is added to the reaction mixture and the mixture is shaken for about 1 hr. The resin is washed with DMF and treated with 3 mmol of 1-iodotetradecane for about 4 hrs. After washing with DMF, the resin is treated with 3 mmol of acetic anhydride and 1 mL of DIEA in 4 mL of DMF for about 0.5 hr. The resin is washed with DMF and treated with 25% piperidine in DMF for 2×20 min to remove the Fmoc protecting group. The resin is washed with DMF and transferred to the reaction vessel of the peptide synthesizer to continue the synthesis. The remaining synthesis and purification procedures for the peptide are the same as those for the synthesis of Example 1.

The syntheses of other compounds of the present invention comprising Asp(1-(4-alkylpiperazine)) or Glu(1-(4-alkylpiperazine)) residue are carried out in an analogous manner as the procedure described for the synthesis of Example 11. Fmoc-Asp(O-tBu)-OH or Fmoc-Glu(O-tBu)-OH amino acid is used for the residue of Asp(1-(4-alkylpiperazine)) or Glu(1-(4-alkylpiperazine)) in the peptide, while Boc-Asp(OcHex)-OH or Boc-Glu(OcHex)-OH amino acid is used for the residue of Asp or Glu. The corresponding iodoalkane is used for the residue of Lys(N_(ε)-(2-(4-alkyl-1-piperazine)-acetyl)) during the alkylation step. If the Asp(1-(4-alkylpiperazine)) or Glu(1-(4-alkylpiperazine)) residue is not at the C-terminus, the peptide fragment immediately prior to the Asp(1-(4-alkylpiperazine)) or Glu(1-(4-alkylpiperazine)) residue is assembled on the resin on the peptide synthesizer first.

EXAMPLE 12 (Aib^(8,35), Arg^(26,34), Asp³⁶(1-tetradecylamino))hGLP-1(7-36)NH₂

The Boc amino acids to be used for this example are the same as those used in Example 5. The first amino acid residue is coupled to the resin manually on a shaker. 2.5 mmol of Fmoc-Asp(O-tBu)-OH is dissolved in 4 mL of 0.5N HBTU in DMF. To the solution is added 1 mL of DIEA. The mixture is shaken for about 2 min. To the solution is then added 0.2 mmol of MBHA (substitution=0.91 mmol/g) resin. The mixture is shaken for about 1 hr. The resin is washed with DMF and treated with 100% TFA for 2×15 min to remove the t-Bu protecting group. The resin is washed with DMF and is treated with HBTU (0.6 mmol) and DIEA (1 mL) in 4 mL of DMF for about 15 min. 0.6 mmol of 1-tetradecaneamine is added to the reaction mixture and the mixture is shaken for about 1 hr. The resin is washed with DMF and treated with 25% piperidine in DMF for 2×20 min to remove the Fmoc protecting group. The resin is washed with DMF and transferred to the reaction vessel of the peptide synthesizer to continue the synthesis. The remaining synthesis and purification procedures for the peptide of this example are the same as those described for the synthesis of Example 1.

The syntheses of other compounds of the present invention containing Asp(1-alkylamino) or Glu(1-alkylamino) residue are carried out in an analogous manner as described for the synthesis of Example 12. Fmoc-Asp(O-tBu)-OH or Fmoc-Glu(O-tBu)-OH amino acid is used for the residue of Asp(1-alkylamino) or Glu(1-alkylamino), respectively, in the peptide, while Boc-Asp(OcHex)-OH or Boc-Glu(OcHex)-OH amino acid is used for the residue of Asp or Glu, respectively. If the Asp(1-alkylamino) or Glu(1-alkylamino) residue is not at the C-terminus, the peptide fragment immediately prior to the Asp(1-alkylamino) or Glu(1-alkylamino) residue is assembled on the resin on the peptide synthesizer first.

EXAMPLE 13 (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-tetradecanoyl),β-Ala³⁷)hGLP-1(7-37)-OH

The Boc amino acids used are the same as those in the synthesis of (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (Example 5). 270 mg of Boc-β-Ala-PAM resin (Novabiochem, San Diego, Calif., substitution=0.74 mmol/g) was used. The Boc protecting group on Boc-β-Ala-PAM resin was deblocked on a shaker with 100% TFA for 2×2 min first. The remainder of the synthesis and purification procedures were the same as that in Example 5. 83.0 mg of the title peptide was obtained as white solid. Purity was 99% based on analytical HPLC analysis. Electro-spray mass spectrometer analysis gave the molecular weight at 3650.5 in agreement with the calculated weight 3650.8.

EXAMPLE 14 (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-tetradecanoyl))hGLP-1(7-36)-OH

The Boc amino acids to be used are the same as those in the synthesis of (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (Example 5). Fmoc-Lys(Boc)-OH (2.5 mmol) is pre-activated with HBTU (2.0 mmol), HOBt (2.0 mmol and DIEA (2.5 ml) in DMF (4 ml) for about 2 min. This amino acid is coupled to 235 mg of PAM resin (Chem-Impex, Wood Dale, Ill.; substitution=0.85 mmol/g) manually on a shaker. The coupling time is about 8 hrs. The remainder of the synthesis and purification procedures are the same as those in Example 5. Electro-spray mass spectrometer analysis gave the molecular weight at 3579.15 in agreement with the calculated weight 3579.5.

The syntheses of other analogs of hGLP-1(7-36)-OH, hGLP-1(7-37)-OH and hGLP-1(7-38)-OH of the instant invention which contain Lys(N_(ε)-alkanoyl) residue can be carried out in an analogous manner according to the procedure described for the synthesis of Example 14. Fmoc-Lys(Boc)-OH amino acid is used for the residue of Lys(N_(ε)-alkanoyl) in the peptide, while Boc-Lys(2ClZ)-OH amino acid is used for the residue of Lys.

EXAMPLE 366 (Aib⁸, β-Ala³⁵, Aec³⁷)hGLP-1(7-37)NH₂

A mixture of MBHA resin (0.2 mmol, substitution=0.91 mmol/g), Fmoc-Aec-OH (0.40 g, 0.829 mmol), HBTU (1.5 mL @ 0.5M in DMF) and DIEA (0.5 mL) in a reaction vessel was shaken on a shaker for 4 h at room temperature. The resin was then washed with DMF and treated with 25% piperidine in DMF for 2×20 min. The resin was washed with DMF and DCM and transferred to the reaction vessel of the peptide synthesizer to continue the assembly of the rest of the peptide according the procedure described for Example 1. The purification procedure was also the same as the one described in Example 1. Electro-spry mass spectrometer analysis gave the molecular weight at 3494.8 in agreement with the calculated molecular weight 3494.99. Purity 93%; Yield 79.1 mg.

EXAMPLE 367 (Aib⁸, β-Ala³⁵, Aec³⁸)hGLP-1(7-38)NH₂

Example 367 was synthesized substantially according to the procedure described for Example 366. MS(ES)=3551.7, calculated MW=3552.04; Purity 97%; Yield 97.4 mg.

EXAMPLE 368 (Aib⁸, β-Ala³⁵, Aec^(37,38))hGLP-1(7-38)NH₂

A mixture of MBHA resin (0.2 mmol, substitution=0.91 mmol/g), Fmoc-Aec-OH (0.289 g, 0.6 mmol), HBTU (1.12 mL @ 0.5M in DMF) and DIEA (0.4 mL) in a reaction vessel was shaken on a shaker for 2 h at room temperature. The resin was then washed with DMF and treated with 30% piperidine in DMF for 2×15 min. The resin was washed with DMF. To the reaction vessel were added Fmoc-Aec-OH (0.289 g, 0.6 mmol), HBTU (1.12 mL @ 0.5M in DMF) and DIEA (0.4 mL). The mixture was shaken at room temperature for 2 h. The resin was washed with DMF and treated with 30% piperidine in DMF for 2×15 min. The resin was washed with DMF and DCM and transferred to the reaction vessel of the peptide synthesizer to continue the assembly of the rest of the peptide according the procedure described for Example 1. The purification procedure was also the same as the one described in Example 1. Electro-spry mass spectrometer analysis gave the molecular weight at 3663.9 in agreement with the calculated molecular weight 3664.26. Purity 100%; Yield 75.3 mg.

EXAMPLE 369 (Aib⁸, Arg^(26,34), β-Ala³⁵, Lys³⁶(N^(ε)-Aec-decanoyl))hGLP-1(7-36)NH₂

A mixture of MBHA resin (0.2 mmol, substitution=0.91 mmol/g), Boc-Lys(Fmoc)-OH (1.17 g, 2.5 mmol), HBTU (4 mL @ 0.5M in DMF) and DIEA (1 mL) in a reaction vessel was shaken on a shaker at room temperature for 10 min. The resin was washed with DMF and treated with 25% piperidine in DMF for 2×15 min. The resin was washed with DMF. To the reaction vessel were added Fmoc-Aec-OH (0.289 g, 0.6 mmol), HBTU (1.12 mL @ 0.5M in DMF) and DIEA (0.4 mL). The mixture was shaken at room temperature for 10 min. The resin was washed with DMF and treated with 30% piperidine in DMF for 2×15 min. The resin was washed with DMF and treated with a mixture of decanoic acid (431 mg, 2.5 mmol), HBTU (4 mL @ 0.5M in DMF) and DIEA (1 mL) for 10 min. The resin was washed with DMF and treated with 100% TFA for 2×2 min. The resin was washed with DMF and DCM and transferred to the reaction vessel of the peptide synthesizer to continue the assembly of the rest of the peptide according the procedure described for Example 1. The purification procedure was also the same as the one described in Example 1. Electro-spry mass spectrometer analysis gave the molecular weight at 3677.0 in agreement with the calculated molecular weight 3677.25. Purity 97.6%; Yield 44.8 mg.

The following examples can be made according to the appropriate procedures described hereinabove.

EXAMPLE 15 (Aib³⁵)hGLP-1(7-36)NH₂ EXAMPLE 16 (β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 17 ((N^(α)-Me-His)⁷, Aib^(8,35))hGLP-1(7-36)NH₂ EXAMPLE 18 ((N^(α)-Me-His)⁷, Aib⁸, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 19 ((N^(α)-Me-His)⁷, Aib^(8,35), Arg^(26,34))hGLP-1(7-36)NH₂ EXAMPLE 20 ((N^(α)-Me-His)⁷, Aib⁸, Arg^(26,34), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 21 (Aib⁸, A6c³⁵)hGLP-1(7-36)NH₂ EXAMPLE 22 (Aib⁸, A5c³⁵)hGLP-1(7-36)NH₂ EXAMPLE 23 (Aib⁸, D-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 24 (Aib^(8,35), A6c³²)hGLP-1(7-36)NH₂ EXAMPLE 25 (Aib^(8,35), A5c³²)hGLP-1(7-36)NH₂ EXAMPLE 26 (Aib^(8,35), Glu²³)hGLP-1(7-36)NH₂ EXAMPLE 27 (Aib 8,24,35)hGLP-1(7-36)NH₂ EXAMPLE 28 (Aib^(8,30,35))hGLP-1(7-36)NH₂ EXAMPLE 29 (Aib^(8,25,35))hGLP-1(7-36)NH₂ EXAMPLE 30 (Aib^(8,35), A6c^(16,20))hGLP-1(7-36)NH₂ EXAMPLE 31 (Aib^(8,35), A6c^(16,29,32))hGLP-1(7-36)NH₂ EXAMPLE 32 (Aib^(8,35), A6c^(20,32))hGLP-1(7-36)NH₂ EXAMPLE 33 (Aib^(8,35), A6c²⁰)hGLP-1(7-36)NH₂ EXAMPLE 34 (Aib^(8,35), Lys²⁵)hGLP-1(7-36)NH₂ EXAMPLE 35 (Aib^(8,24,35), A6c²⁰)hGLP-1(7-36)NH₂ EXAMPLE 36 (Aib^(8,35), A6c^(29,32))hGLP-1(7-36)NH₂ EXAMPLE 37 (Aib^(8,24,35), A6c^(29,32))hGLP-1(7-36)NH₂ EXAMPLE 38 (Aib^(8,35), A6c¹²)hGLP-1(7-36)NH₂ EXAMPLE 39 (Aib^(8,35), Cha²⁰)hGLP-1(7-36)NH₂ EXAMPLE 40 (Aib^(8,35), A6c³³)hGLP-1(7-36)NH₂ EXAMPLE 41 (Aib^(8,35), A6c^(20,32))hGLP-1(7-36)NH₂ EXAMPLE 42 (Aib⁸, A6c^(16,20), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 43 (Aib^(8,35), β-Ala²²)hGLP-1(7-36)NH₂ EXAMPLE 44 (Aib^(8,22,35))hGLP-1(7-36)NH₂ EXAMPLE 45 (Aib^(8,35), Glu²³, A6c³²)hGLP-1(7-36)NH₂ EXAMPLE 46 (Aib^(8,24,35), Glu²³, A6c³²)hGLP-1(7-36)NH₂ EXAMPLE 47 (Aib^(8,24,25,35), Glu²³, A6c³²)hGLP-1(7-36)NH₂ EXAMPLE 48 (Aib^(8,24,25,35), A6c^(16,20,32), Glu²³)hGLP-1(7-36)NH₂ EXAMPLE 49 (Aib⁸, A6c³², β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 50 (Aib⁸, A5c³², β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 51 (Aib⁸, Glu²³, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 52 (Aib^(8,24), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 53 (Aib^(8,30), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 54 (Aib^(8,25), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 55 (Aib⁸, A6c^(16,20), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 56 (Aib⁸, A6c^(16,29,32), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 57 (Aib⁸, A6c^(20,32), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 58 (Aib⁸, A6c²⁰, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 59 (Aib⁸, Lys²⁵, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 60 (Aib^(8,24), A6c²⁰, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 61 (Aib⁸, A6c^(29,32), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 62 (Aib^(8,24), A6c^(29,32), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 63 (Aib⁸, A6c¹², β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 64 (Aib⁸, Cha²⁰, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 65 (Aib⁸, A6c³³, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 66 (Aib⁸, A6c^(20,32), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 67 (Aib⁸, β-Ala^(22,35))hGLP-1(7-36)NH₂ EXAMPLE 68 (Aib^(8,22), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 69 (Aib⁸, Glu²³, A6c³², β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 70 (Aib^(8,24), Glu²³, A6c³², β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 71 (Aib^(8,24), Glu²³ , A6c³² , Lys³⁴(N_(ε)-octanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 72 (Aib^(8,24,25), Glu²³, A6c³², β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 73 (Aib^(8,24,25), A6c^(16,20,32), Glu²³, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 74 (Aib^(8,35), D-Arg³⁶)hGLP-1(7-36)NH₂ EXAMPLE 75 (Aib^(8,35), D-Lys³⁶)hGLP-1(7-36)NH₂ EXAMPLE 76 (Aib⁸, β-Ala³⁵, D-Arg³⁶)hGLP-1(7-36)NH₂ EXAMPLE 77 (Aib⁸, β-Ala³⁵, D-Lys³⁶)hGLP-1(7-36)NH₂ EXAMPLE 78 (Aib^(8,35), Arg^(26,34))hGLP-1(7-36)NH₂ EXAMPLE 79 (Aib⁸, Arg^(26,34), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 80 (Aib^(8,35), Arg^(25,26,34))hGLP-1(7-36)NH₂ EXAMPLE 81 (Aib⁸, Arg^(25,26,34), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 82 (Aib⁸, Arg^(26,34), β-Ala³⁵, Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)OH EXAMPLE 83 (Aib^(8,35), Arg^(26,34), Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-37)OH EXAMPLE 84 (Aib^(8,35,37), Arg^(26,34), Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-37)OH EXAMPLE 85 (Aib^(8,35), Arg^(26,34), Lys³⁶(N^(ε)-tetradecanoyl), D-Ala³⁷)hGLP-1(7-37)OH EXAMPLE 86 (Aib^(8,35,37), Arg^(26,34), Lys³⁸(N^(ε)-tetradecanoyl))hGLP-1(7-38)OH EXAMPLE 87 (Aib^(8,35), Arg^(26,34), β-Ala³⁷, Lys³⁸(N^(ε)-tetradecanoyl))hGLP-1(7-38)OH EXAMPLE 88 (Aib^(8,35), Arg^(26,34), Lys³⁸(N^(ε)-tetradecanoyl))hGLP-1(7-38)OH EXAMPLE 89 (Aib⁸, Arg^(26,34), Lys³⁶(N^(ε)-tetradecanoyl), β-Ala³⁷)hGLP-1(7-37)OH EXAMPLE 90 (Aib^(8,37), Arg^(26,34), Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-37)OH EXAMPLE 91 (Aib^(8,35), Arg^(26,34), Ado³⁷)hGLP-1(7-37)OH EXAMPLE 92 (Aib^(8,35), Arg^(26,34), Ado³⁷)hGLP-1(7-37)NH₂ EXAMPLE 93 (Aib⁸, Arg^(26,34), Lys³⁶(N^(ε)-tetradecanoyl), D-Ala³⁷)hGLP-1(7-37)OH EXAMPLE 94 (Aib^(8,37), Arg^(26,34), Lys³⁸(N^(ε)-tetradecanoyl))hGLP-1(7-38)OH EXAMPLE 95 (Aib⁸, Arg^(26,34), β-Ala³⁷, Lys³⁸(N^(ε)-tetradecanoyl))hGLP-1(7-38)OH EXAMPLE 96 (Aib^(8,35), Lys²⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 97 (Aib^(8,35), Lys²⁶(N^(ε)-tetradecanoyl))hGLP-1 (7-36)NH₂ EXAMPLE 98 (Aib^(8,35), Lys²⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 99 (Aib⁸, Lys²⁶(N^(ε)-octanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 100 (Aib⁸, Lys²⁶(N^(ε)-tetradecanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 101 (Aib⁸, Lys²⁶(N^(ε)-hexadecanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 102 (Aib^(8,35), Lys²⁶(N^(ε)-octanoyl), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 103 (Aib^(8,35), Lys²⁶(N^(ε)-tetradecanoyl), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 104 (Aib^(8,35), Lys²⁶(N^(ε)-hexadecanoyl), Arg³⁵)hGLP-1(7-36)NH₂ EXAMPLE 105 (Aib^(8,35), Lys²⁶(N^(ε)-decanoyl), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 106 (Aib^(8,35), Lys²⁵, Lys²⁶(N^(ε)-octanoyl), Arg³⁵)hGLP-1(7-36)NH₂ EXAMPLE 107 (Aib^(8,35), Lys²⁵, Lys²⁶(N^(ε)-tetradecanoyl), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 108 (Aib^(8,35), Lys²⁵, Lys²⁶(N^(ε)-hexadecanoyl), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 109 (Aib^(8,35), Arg^(25,34), Lys²⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 110 (Aib^(8,35), Arg^(25,34), Lys²⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 111 (Aib^(8,35), Arg^(25,34), Lys²⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 112 (Aib^(8,35), Arg^(25,34), Lys²⁸(N^(ε)-decanoyl))hGLP-1(7-36)NH₂ EXAMPLE 113 (Aib⁸, Lys²⁶(N^(ε)-octanoyl), Arg³⁴, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 114 (Aib⁸, Lys²⁶(N^(ε)-tetradecanoyl), Arg³⁴, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 115 (Aib⁸, Lys²⁶(N^(ε)-hexadecanoyl), Arg³⁴, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 116 (Aib⁸, Lys²⁶(N^(ε)-decanoyl), Arg³⁴, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 117 (Aib^(8,35), Lys³⁴(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 118 (Aib^(8,35), Lys³⁴(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 119 (Aib^(8,35), Lys³⁴(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 120 (Aib^(8,35), Arg²⁶, Lys³⁴(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 121 (Aib^(8,35), Arg²⁶, Lys³⁴(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 122 (Aib^(8,35), Arg²⁶, Lys³⁴(N^(ε)-decanoyl))hGLP-1(7-36)NH₂ EXAMPLE 123 (Aib^(8,35), Arg^(25,26), Lys³⁴(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 124 (Aib^(8,35), Arg^(25,26), Lys³⁴(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 125 (Aib^(8,35), Arg^(25,26), Lys³⁴(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 126 (Aib^(8,35), Arg^(25,26), Lys³⁴(N^(ε)-decanoyl))hGLP-1(7-36)NH₂ EXAMPLE 127 (Aib^(8,35), Lys²⁵, Arg²⁶, Lys³⁴(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 128 (Aib^(8,35), Lys²⁵, Arg²⁶, Lys³⁴(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 129 (Aib^(8,35), Lys²⁵, Arg²⁶, Lys³⁴(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 130 (Aib-^(8,35), Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 131 (Aib^(8,35), Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 132 (Aib^(8,35), Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 133 (Aib^(8,35), Arg²⁶, Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 134 (Aib^(8,35), Arg²⁶, Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 135 (Aib^(8,35), Arg²⁶, Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 136 (Aib^(8,35), Arg^(26,34), Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 137 (Aib^(8,35), Arg^(26,34), Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 138 (Aib^(8,35), Arg^(26,34), Lys³⁸(N^(ε)-octanoyl))hGLP-1(7-38)NH₂ EXAMPLE 139 (Aib^(8,35), Arg^(26,34), Lys³⁸(N^(ε)-decanoyl))hGLP-1(7-38)NH₂ EXAMPLE 140 (Aib^(8,35), Arg^(26,34), Lys³⁸(N^(ε)-tetradecanoyl))hGLP-1(7-38)NH₂ EXAMPLE 141 (Aib^(8,35), Arg^(26,34), Lys³⁸(N^(ε)-hexadecanoyl))hGLP-1(7-38)NH₂ EXAMPLE 142 (Aib^(8,35,37), Arg^(25,26,34), Lys³⁸(N^(ε)-octanoyl))hGLP-1(7-38)NH₂ EXAMPLE 143 (Aib^(8,35,37), Arg^(25,26,34), Lys³⁸(N^(ε)-decanoyl))hGLP-1(7-38)NH₂ EXAMPLE 144 (Aib^(8,35,37), Arg^(25,26,34), Lys³⁸(N^(ε)-tetradecanoyl))hGLP-1(7-38)NH₂ EXAMPLE 145 (Aib^(8,35,37), Arg^(25,26,34), Lys³⁸(N^(ε)-hexadecanoyl))hGLP-1(7-38)NH₂ EXAMPLE 146 (Aib^(8,35,37), Arg^(26,34), Lys³⁸(N^(ε)-octanoyl))hGLP 1(7-38)NH₂ EXAMPLE 147 (Aib^(8,35,37), Arg^(26,34), Lys³⁸(N^(ε)-decanoyl))hGLP-1(7-38)NH₂ EXAMPLE 148 (Aib^(8,35,37), Arg^(26,34), Lys³⁸(N^(ε)-hexadecanoyl))hGLP-1(7-38)NH₂ EXAMPLE 149 (Aib^(8,35,37), Arg^(25,26,34), Lys³⁸(N^(ε)-octanoyl))hGLP-1(7-38)NH₂ EXAMPLE 150 (Aib^(8,35,37), Arg^(25,26,34), Lys³⁸(N^(ε)-decanoyl))hGLP-1(7-38)NH₂ EXAMPLE 151 (Aib^(8,35,37), Arg^(25,26,34), Lys³⁸(N^(ε)-tetradecanoyl))hGLP-1(7-38)NH₂ EXAMPLE 152 (Aib^(8,35,37), Arg^(25,26,34), Lys³⁸(N^(ε)-hexadecanoyl))hGLP-1(7-38)NH₂ EXAMPLE 153 (Aib^(8,35), Lys²⁵, Arg^(26,34), Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 154 (Aib^(8,35), Lys²⁵, Arg^(26,34), Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 155 (Aib^(8,35), Lys²⁵, Arg^(26,34), Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 156 (Aib^(8,35), Arg^(25,26,34), Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 157 (Aib^(8,35), Arg^(25,26,34), Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 158 (Aib^(8,35), Arg^(25,26,34), Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 159 (Aib^(8,35), Arg^(25,26,34), Lys³⁶(N^(ε)-decanoyl))hGLP-1(7-36)NH₂ EXAMPLE 160 (Aib³, Lys³⁴(N^(ε)-octanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 161 (Aib⁸, Lys³⁴(N^(ε)-tetradecanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 162 (Aib⁸, Lys³⁴(N^(ε)-hexadecanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 163 (Aib⁸, A6c³², Lys³⁴(N_(ε)-octanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 164 (Aib⁸, Glu²³, Lys³⁴(N_(ε)-octanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 165 (Aib⁸, Glu²³, A6c³², Lys³⁴(N_(ε)-octanoyl), β-Ala³⁵)hGLP-1(7-36)NH EXAMPLE 166 (Aib⁸, Arg²⁶, Lys³⁴(N^(ε)-octanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 167 (Aib⁸, Arg²⁶, Lys³⁴(N^(ε)-tetradecanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 168 (Aib⁸, Arg²⁶, Lys³⁴(N^(ε)-hexadecanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 169 (Aib⁸, Arg²⁶, Lys³⁴(N^(ε)-decanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 170 (Aib⁸, Arg^(25,26), Lys³⁴(N^(ε)-octanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 171 (Aib⁸, Arg^(25,26), Lys³⁴(N^(ε)-tetradecanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 172 (Aib⁸, Arg^(25,26), Lys³⁴(N^(ε)-hexadecanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 173 (Aib⁸, Arg^(25,26), Lys³⁴(N^(ε)-decanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 174 (Aib⁸, Lys²⁵, Arg²⁶, Lys³⁴(N^(ε)-octanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 175 (Aib⁸, Lys²⁵, Arg²⁶, Lys³⁴(N^(ε)-tetradecanoyl), β-Ala 3)hGLP-1(7-36)NH₂ EXAMPLE 176 (Aib⁸, Lys²⁵, Arg²⁶, Lys³⁴(N^(ε)hexadecanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 177 (Aib⁸, β-Ala³⁵, Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 178 (Aib³, β-Ala³⁵, Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 179 (Aib⁸, β-Ala³⁵, Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 180 (Aib⁸, Arg²⁶, β-Ala³⁵, Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 181 (Aib⁸, Arg²⁶, β-Ala³⁵, Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 182 (Aib⁸, Arg²⁶, β-Ala³⁶, Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 183 (Aib⁸, Arg^(26,34), β-Ala³⁵, Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 184 (Aib⁸, Arg^(26,34), β-Ala³⁵, Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 185 (Aib⁸, Arg^(26,34), β-Ala³⁵, Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 186 (Aib⁸, Arg^(26,34), β-Ala³⁵, Lys³⁶(N^(ε)-decanoyl))hGLP-1(7-36)NH₂ EXAMPLE 187 (Aib⁸, Lys²⁵, Arg^(26,34), β-Ala³⁵, Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 188 (Aib⁸, Lys²⁵, Arg^(26,34), Lys³⁶(N^(ε)-tetradecanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 189 (Aib⁸, Lys²⁵, Arg^(26,34), β-Ala³⁵, Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 190 (Aib⁸, Arg^(25,26,34), β-Ala³⁵, Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 191 (Aib⁸, Arg^(25,26,34), β-Ala³⁵, Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 192 (Aib⁸, Arg^(25,26,34), β-Ala³⁵, Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 193 (Aib⁸, Arg^(25,26,34), β-Ala³⁵, Lys³⁶(N^(ε)-decanoyl))hGLP-1(7-36)NH₂ EXAMPLE 194 (Aib^(8,35), Lys²⁶(N^(ε)-octanoyl), A6c³², Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 195 (Aib^(8,35), Lys²⁶(N^(ε)-tetradecanoyl), A6c³², Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 196 (Aib^(8,35), Lys²⁶(N^(ε)-hexadecanoyl), A6c³², Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 197 (Aib^(8,35), A6c³², Lys³⁴(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 198 (Aib^(8,35), A6c³², Lys³⁴(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 199 (Aib^(8,35), A6c³², Lys³⁴(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 200 (Aib^(8,35), Arg²⁶, A6c³², Lys³⁴(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 201 (Aib^(8,35), Arg²⁶, A6c³², Lys³⁴(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 202 (Aib^(8,35), A6c³², Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 203 (Aib^(8,35), A6c³², Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 204 (Aib^(8,35), A6c³², Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 205 (Aib^(8,35), Arg²⁶, A6c³², Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 206 (Aib^(8,35), Arg²⁶, A6c³², Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 207 (Aib^(8,35), Arg²⁶, A6c³², Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 208 (Aib^(8,35), Arg^(26,34), A6c³², Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 209 (Aib^(8,35), Arg^(26,34), A6c³², Lys³⁶(N^(ε)-decanoyl))hGLP-1(7-36)NH₂ EXAMPLE 210 (Aib^(8,35), Arg^(26,34), A6c³², Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 211 (Aib^(8,35), Arg^(26,34), A6c³², Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 212 (Aib^(8,24,35), Lys²⁶(N^(ε)-octanoyl), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 213 (Aib^(8,24,35), Lys²⁶(N^(ε)-tetradecanoyl), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 214 (Aib^(8,24,35), Lys²⁶(N^(ε)-hexadecanoyl), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 215 (Aib^(8,24,35), Arg²⁶, Lys³⁴(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 216 (Aib^(8,24,35), Arg²⁶, Lys³⁴(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 217 (Aib^(8,24,35), Arg²⁶, Lys³⁴(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 218 (Aib^(8,24,35), Arg^(26,34), Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 219 (Aib^(8,24,35), Arg^(26,34), Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 220 (Aib^(8,24,35), Arg^(26,34), Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 221 (Aib^(8,24,35), Glu²³, A6C³², Lys³⁴(N_(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 222 (Aib^(8,35), Glu²³, Lys²⁶(N^(ε)-octanoyl), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 223 (Aib^(8,35), Glu²³, Lys²⁶(N^(ε)-tetradecanoyl), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 224 (Aib^(8,35), Glu²³, Lys²⁶(N^(ε)-hexadecanoyl), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 225 (Aib^(8,35), Glu²³, Lys³⁴(N_(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 226 (Aib^(8,35), Glu²³, A6c³², Lys³⁴(N_(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 227 (Aib^(8,35), Glu²³, Arg²⁶, Lys³⁴(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 228 (Aib^(8,35), Glu²³, Arg²⁶, Lys³⁴(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 229 (Aib^(8,35), Glu²³, Arg²⁶, Lys³⁴(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 230 (Aib^(8,35), Glu²³, Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 231 (Aib^(8,35), Glu²³, Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 232 (Aib^(8,35), Glu²³, Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 233 (Aib^(8,35), Glu²³, Arg^(26,34), Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 234 (Aib^(8,35), Glu²³, Arg^(26,34), Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 235 (Aib^(8,35), Glu²³, Arg^(26,34), Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 236 (Aib^(8,30,35), Lys²⁶(N^(ε)-octanoyl), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 237 (Aib^(8,30,35), Lys²⁶(N^(ε)-tetradecanoyl), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 238 (Aib^(8,30,35), Lys²⁶(N^(ε)-hexadecanoyl), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 239 (Aib^(8,30,35), Arg²⁶, Lys³⁴(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 240 (Aib^(8,30,35), Arg²⁶, Lys³⁴(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 241 (Aib^(8,30,35), Arg²⁶, Lys³⁴(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 242 (Aib^(8,30,35), Arg^(26,34), Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 243 (Aib^(8,30,35), Arg^(26,34), Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 244 (Aib^(8,30,35), Arg^(26,34), Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 245 (Aib^(8,35), Glu²³, A6c³², Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 246 (Aib^(8,35), Glu²³, A6c³², Lys³⁶(N^(ε)-tetradecanoyl))hGLP 1(7-36)NH₂ EXAMPLE 247 (Aib^(8,35), Glu²³, A6C³², Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 248 (Aib^(8,35), Glu²³, Arg^(26,34), A6c³², Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 249 (Aib^(8,35), Glu²³, Arg^(26,34), A6c³², Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 250 (Aib^(8,35), Glu²³, Arg^(26,34), A6c³², Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 251 (Aib^(8,24,35), Glu²³, Arg^(26,34), A6c³², Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 252 (Aib^(8,24,35), Glu²³, Arg^(26,34), A6c³², Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 253 (Aib^(8,24,35), Glu²³, Arg^(26,34), A6c³², Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 254 (Aib^(8,24,30,35), Glu²³, Arg^(26,34), A6c³², Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ EXAMPLE 255 (Aib^(8,24,30,35), Glu²³, Arg^(26,34), A6c³², Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 256 (Aib^(8,24,30,35), Glu²³, Arg^(26,34), A6c³², Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 257 ((N^(α)-HEPES-His)⁷, Aib³⁵)hGLP-1(7-36)NH₂ EXAMPLE 258 ((N^(α)-HEPES-His)⁷, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 259 ((N^(α)-HEPES-His)⁷, Aib⁸, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 260 ((N^(α)-HEPA-His)⁷, Aib³⁵)hGLP-1(7-36)NH₂ EXAMPLE 261 ((N^(α)-HEPA-His)⁷, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 262 ((N^(α)-HEPA-His)⁷, Aib⁸, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 263 ((N^(α)-tetradecanoyl-His)⁷, Aib³⁵)hGLP-1(7-36)NH₂ EXAMPLE 264 ((N^(α)-tetradecanoyl-His)⁷, β-Ala³⁵)hGLP-1(7-36)N H₂ EXAMPLE 265 ((N^(α)-tetradecanoyl-His)⁷, Aib^(8,35))hGLP-1(7-36)NH₂ EXAMPLE 266 ((N^(α)-tetradecanoyl-His)⁷, Aib⁸, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 267 ((N^(α)-tetradecanoyl-His)⁷, Arg^(26,34), Aib³⁵)hGLP-1(7-36)NH₂ EXAMPLE 268 ((N^(α)-tetradecanoyl-His)⁷, Arg^(26,34), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 269 ((N^(α)-tetradecanoyl-His)⁷, Aib^(8,35), Arg^(26,34))hGLP-1(7-36)NH₂ EXAMPLE 270 ((N^(α)-tetradecanoyl-His)⁷, Aib⁸, Arg^(26,34), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 271 ((N^(α)-tetradecanoyl-His)⁷, Arg^(25,26,34), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 272 ((N^(α)-tetradecanoyl-His)⁷, Aib^(8,35), Arg^(25,26,34))hGLP-1(7-36)NH₂ EXAMPLE 273 ((N^(α)-tetradecanoyl-His)⁷, Aib⁸, Arg^(25,26,34), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 274 (Aib^(8,35), Lys²⁶(N^(ε)-octanesulfonyl), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 275 (Aib^(8,35), Lys²⁶(N^(ε)-dodecanesulfonyl), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 276 (Aib^(8,35), Lys²⁶(N^(ε)-hexadecanesulfonyl), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 277 (Aib^(8,35), Arg²⁶, Lys³⁴(N^(ε)-octanesulfonyl))hGLP-1(7-36)NH₂ EXAMPLE 278 (Aib^(8,35), Arg²⁶, Lys³⁴(N^(ε)-dodecanesulfonyl))hGLP-1(7-36)NH₂ EXAMPLE 279 (Aib^(8,35), Arg²⁶, Lys³⁴(N^(ε)-hexadecanesulfonyl))hGLP-1(7-36)NH₂ EXAMPLE 280 (Aib^(8,35), Arg^(26,34), Lys³⁸(N^(ε)-octanesulfonyl))hGLP-1(7-36)NH₂ EXAMPLE 281 (Aib^(8,35), Arg^(26,34), Lys³⁶(N^(ε)-hexadecanesulfonyl))hGLP-1(7-36)NH₂ EXAMPLE 282 (Aib^(8,35), Asp²⁶(1-(4-decylpiperazine)), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 283 (Aib^(8,35), Asp²⁶(1-(4-dodecylpiperazine)), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 284 (Aib^(8,35), Asp²⁶(1-(4-tetradecylpiperazine)), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 285 (Aib^(8,35), Asp²⁶(1-(4-hexadecylpiperazine)), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 286 (Aib^(8,35), Arg²⁶, Asp³⁴(1-(4-decylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 287 (Aib^(8,35), Arg²⁶, Asp³⁴(1-(4-dodecylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 288 (Aib^(8,35), Arg²⁶, Asp³⁴(1-(4-tetradecylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 289 (Aib^(8,35), Arg²⁶, Asp³⁴(1-(4-hexadecylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 290 (Aib^(8,35), Arg^(26,34), Asp³⁶(1-(4-decylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 291 (Aib^(8,35), Arg^(26,34), Asp³⁶(1-(4dodecylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 292 (Aib^(8,35), Arg^(26,34), Asp³⁸(1-(4-hexadecylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 293 (Aib^(8,35), Arg^(26,34), Asp³⁸(1-(4-decylpiperazine)))hGLP-1(7-38)NH₂ EXAMPLE 294 (Aib^(8,35), Arg^(26,34), Asp³⁸(1-(4-dodecylpiperazine)))hGLP-1(7-38)NH₂ EXAMPLE 295 (Aib^(8,35), Arg^(26,34), Asp³⁸(1-(4-tetradecylpiperazine)))hGLP-1(7-38)NH₂ EXAMPLE 296 (Aib^(8,35), Arg^(26,34), Asp³⁸(1-(4-hexadecylpiperazine)))hGLP-1(7-38)NH₂ EXAMPLE 297 (Aib^(8,35,37), Arg^(26,34), Asp³⁸(1-(4-decylpiperazine)))hGLP-1(7-38)NH₂ EXAMPLE 298 (Aib^(8,35,37), Arg^(26,34), Asp³⁸(1-(4-dodecylpiperazine)))hGLP-1(7-38)NH₂ EXAMPLE 299 (Aib^(8,35,37), Arg^(26,34), Asp³⁸(1-(4-tetradecylpiperazine)))hGLP-1(7-38)NH₂ EXAMPLE 300 (Aib^(8,35,37), Arg^(26,34), Asp³⁸(1-(4-hexadecylpiperazine)))hGLP-1(7-38)NH₂ EXAMPLE 301 (Aib^(8,35), Arg^(25,34), Asp²⁶(1-(4-decylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 302 (Aib^(8,35), Arg^(25,34), Asp²⁶(1-(4-dodecylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 303 (Aib^(8,35), Arg^(25,34), Asp²⁶(1-(4-tetradecylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 304 (Aib^(8,35), Arg^(25,34), Asp²⁶(1-(4-hexadecylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 305 (Aib^(8,35), Arg^(25,26), Asp³⁴(1-(4-decylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 306 (Aib^(8,35), Arg^(25,26), Asp³⁴(1-(4-dodecylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 307 (Aib^(8,35), Arg^(25,26), Asp³⁴(1-(4-tetradecylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 308 (Aib^(8,35), Arg^(25,26), Asp³⁴(1-(4-hexadecylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 309 (Aib^(8,35), Arg^(25,26,34), Asp³⁶(1-(4-decylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 310 (Aib^(8,35), Arg^(25,26,34), Asp³⁶(1-(4-dodecylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 311 (Aib^(8,35), Arg^(25,26,34), Asp³⁶(1-(4-tetradecylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 312 (Aib^(8,35), Arg^(25,26,34), Asp³⁶(1-(4-hexadecylpiperazine)))hGLP-1(7-36)NH₂ EXAMPLE 313 (Aib^(8,35), Arg^(25,26,34), Asp³⁸(1-(4-decylpiperazine)))hGLP-1(7-38)NH₂ EXAMPLE 314 (Aib^(8,35), Arg^(25,26,34), Asp³⁸(1-(4-dodecylpiperazine)))hGLP-1(7-38)NH₂ EXAMPLE 315 (Aib^(8,35), Arg^(25,26,34), Asp³⁸(1-(4-tetradecylpiperazine)))hGLP-1(7-38)NH₂ EXAMPLE 316 (Aib^(8,35), Arg^(25,26,34), Asp³⁸(1-(4-hexadecylpiperazine)))hGLP-1(7-38)NH₂ EXAMPLE 317 (Aib^(8,35,37), Arg^(25,26,34), Asp³⁸(1-(4-decylpiperazine)))hGLP-1(7-38)NH₂ EXAMPLE 318 (Aib^(8,35,37), Arg^(25,26,34), Asp³⁸(1-(4-dodecylpiperazine)))hGLP-1(7-38)NH₂ EXAMPLE 319 (Aib^(8,35,37), Arg^(25,26,34), Asp³⁸(1-(4-tetradecylpiperazine)))hGLP-1(7-38)NH₂ EXAMPLE 320 (Aib^(8,35,37), Arg^(25,26,34), Asp³⁸(1-(4-hexadecylpiperazine)))hGLP-1(7-38)NH₂ EXAMPLE 321 (Aib^(8,35), Arg^(26,34), Glu³⁶(1-dodecylamino))hGLP-1(7-36)NH₂ EXAMPLE 322 (Aib^(8,35), Glu²⁶(1-dodecylamino), Arg³⁴)hGLP-1(7-36)NH₂ EXAMPLE 323 (Aib^(8,35), Arg²⁶, Glu³⁴(1-dodecylamino))hGLP-1(7-36)NH₂ EXAMPLE 324 (Aib^(8,35,37), Arg^(26,34), Glu³⁸(1-dodecylamino))hGLP-1(7-38)NH₂ EXAMPLE 325 (Aib^(8,35), Arg³⁴, Lys²⁶(N^(ε)-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 326 (Aib^(8,35), Arg³⁴, Lys²⁶(N^(ε)-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 327 (Aib^(8,35), Arg³⁴, Lys²⁶(N^(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 328 (Aib^(8,35), Arg³⁴, Lys²⁶(N^(ε)-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 329 (Aib^(8,35), Arg²⁶, Lys³⁴(N^(ε)-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 330 (Aib^(8,35), Arg²⁶, Lys³⁴(N^(ε)-(2-(4-dodecyl-1-piperazine)-acetyl))hGLP-1(7-36)NH₂ EXAMPLE 331 (Aib^(8,35), Arg²⁶, Lys³⁴(N^(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 332 (Aib^(8,35), Arg²⁶, Lys³⁴(N^(ε)-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 333 (Aib^(8,35), Arg^(26,34), Lys³⁶(N^(ε)-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 334 (Aib^(8,35), Arg^(26,34), Lys³⁶(N^(ε)-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 335 (Aib^(8,35), Arg^(26,34), Lys³⁶(N^(ε)-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 336 (Aib^(8,35), Arg^(26,34), Lys³⁸(N^(ε)-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂ EXAMPLE 337 (Aib^(8,35), Arg^(26,34), Lys³⁸(N^(ε)-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂ EXAMPLE 338 (Aib^(8,35), Arg^(26,34), Lys³⁸(N^(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂ EXAMPLE 339 (Aib^(8,35), Arg^(26,34), Lys³⁸(N^(ε)-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂ EXAMPLE 340 (Aib^(8,35,37), Arg^(26,34), Lys³⁸(N^(ε)-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂ EXAMPLE 341 (Aib^(8,35,37), Arg^(26,34), Lys³⁸(N^(ε)-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂ EXAMPLE 342 (Aib^(8,35,37), Arg^(26,34), Lys³⁸(N^(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂ EXAMPLE 343 (Aib^(8,35,37), Arg^(26,34), Lys³⁸(N^(ε)-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂ EXAMPLE 344 (Aib^(8,35), Arg^(25,34), Lys²⁶(N^(ε)-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 345 (Aib^(8,35), Arg^(25,34), Lys²⁶(N^(ε)-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 346 (Aib^(8,35), Arg^(25,34), Lys²⁶(N^(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 347 (Aib^(8,35), Arg^(25,34), Lys²⁶(N^(ε)-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 348 (Aib^(8,35), Arg^(25,26), Lys³⁴(N^(ε)-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 349 (Aib^(8,35), Arg^(25,26), Lys³⁴(N^(ε)-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 350 (Aib^(8,35), Arg^(25,26), Lys³⁴(N^(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 351 (Aib^(8,35), Arg^(25,26), Lys³⁴(N^(ε)-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 352 (Aib^(8,35), Arg^(25,26,34), Lys³⁶(N^(ε)-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 353 (Aib^(8,35), Arg^(25,26,34), Lys³⁶(N^(ε)-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 354 (Aib^(8,35), Arg^(25,26,34), Lys³⁶(N^(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 355 (Aib^(8,35), Arg^(25,26,34), Lys³⁶(N^(ε)-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ EXAMPLE 356 (Aib^(8,35), Arg^(25,26,34), Lys³⁸(N^(ε)-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂ EXAMPLE 357 (Aib^(8,35), Arg^(25,26,34), Lys³⁸(N^(ε)-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂ EXAMPLE 358 (Aib^(8,35), Arg^(25,26,34), Lys³⁸(N^(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂ EXAMPLE 359 (Aib^(8,35), Arg^(25,26,34), Lys³⁸(N^(ε)-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂ EXAMPLE 360 (Aib^(8,35,37), Arg^(25,26,34), Lys³⁸(N^(ε)-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂ EXAMPLE 361 (Aib^(8,35,37), Arg^(25,26,34), Lys³⁸(N^(ε)-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂ EXAMPLE 362 (Aib^(8,35,37), Arg^(25,26,34), Lys³⁸(N^(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂ EXAMPLE 363 (Aib^(8,35,37), Arg^(25,26,34), Lys³⁸(N^(ε)-(2-(4-hexadecyl-1-piperazine)-acetyl))hGLP-1(7-38)NH₂ EXAMPLE 364 (Aib^(8,35), Arg^(26,34), Lys³⁶(N^(ε)-decanoyl))hGLP-1(7-36)OH EXAMPLE 365 (Aib^(8,35), Lys²⁵, Arg^(26,34), Lys³⁶(N^(ε)-decanoyl))hGLP-1(7-36)OH EXAMPLE 370 (Aib^(8,35), Arg^(26,34), Ava³⁷, Ado³⁸)hGLP-1(7-38)NH₂ EXAMPLE 371 (Aib^(8,35), Arg^(26,34), Asp³⁷, Ava³⁸, Ado³⁹)hGLP-1(7-39)NH₂ EXAMPLE 372 (Aib^(8,35), Arg^(26,34), Aun³⁷)hGLP-1(7-37)NH₂ EXAMPLE 373 (Aib^(8,17,35))hGLP-1(7-36)NH₂ EXAMPLE 374 (Aib⁸, Arg^(26,34), β-Ala³⁵, D-Asp³⁷, Ava³⁸, Aun³⁹)hGLP-1(7-39)NH₂ EXAMPLE 375 (Gly⁸, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 376 (Ser⁸, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 377 (Aib⁸, Glu^(22,23), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 378 (Gly⁸, Aib³⁵)hGLP-1(7-36)NH₂ EXAMPLE 379 (Aib⁸, Lys¹⁸, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 380 (Aib⁸, Leu²⁷, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 381 (Aib⁸, Lys³³, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 382 (Aib⁸, Lys¹⁸, Leu²⁷, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 383 (Aib⁸, D-Arg³⁶)hGLP-1(7-36)NH₂ EXAMPLE 384 (Aib⁸, β-Ala³⁵, D-Arg³⁷)hGLP-1(7-37)NH₂ EXAMPLE 385 (Aib^(8,27), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 386 (Aib^(8,27), β-Ala^(35,37), Arg³⁸)hGLP-1(7-38)NH₂ EXAMPLE 387 (Aib^(8,27), β-Ala^(35,37), Arg^(38,39))hGLP-1(7-39)NH₂ EXAMPLE 388 (Aib⁸, Lys^(18,27), β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 389 (Aib⁸, Lys²⁷, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 390 (Aib⁸, β-Ala³⁵, Arg³⁸)hGLP-1(7-38)NH₂ EXAMPLE 391 (Aib⁸, Arg^(26,34), β-Ala³⁵,)hGLP-1(7-36)NH₂ EXAMPLE 392 (Aib⁸, D-Arg³⁵)hGLP-1(7-36)NH₂ EXAMPLE 393 (Aib⁸, β-Ala³⁵, Arg³⁷)hGLP-1(7-37)NH₂ EXAMPLE 394 (Aib⁸, Phe³¹, β-Ala³⁵)hGLP-1(7-36)NH₂ EXAMPLE 395 (Aib^(8,35), Phe³¹)hGLP-1(7-36)NH₂ EXAMPLE 396 (Aib^(8,35), Nal³¹)hGLP-1(7-36)NH₂ EXAMPLE 397 (Aib^(8,35), Nal^(28,31))hGLP-1(7-36)NH₂ EXAMPLE 398 (Aib^(8,35), Arg^(26,34), Nal³¹)hGLP-1(7-36)NH₂ EXAMPLE 399 (Aib^(8,35), Arg^(26,34), Phe³¹)hGLP-1(7-36)NH₂ EXAMPLE 400 (Aib^(8,35), Nal^(19,31))hGLP-1(7-36)NH₂ EXAMPLE 401 (Aib^(8,35), Nal^(12,31))hGLP-1(7-36)NH₂ EXAMPLE 402 (Aib^(8,35), Lys³⁶(N^(ε)-decanoyl))hGLP-1(7-36) NH₂ EXAMPLE 403 (Aib^(8,35), Arg³⁴, Lys²⁶(N^(ε)-decanoyl))hGLP-1(7-36)NH₂ EXAMPLE 404 (Aib^(8,35), Arg^(26,34) Lys³⁶(N^(ε)-dodecanoyl))hGLP-1(7-36)NH₂ EXAMPLE 405 (Aib⁸, B-Ala³⁵, Ser³⁷(O-decanoyl))hGLP1(7-37)-NH₂ EXAMPLE 406 (Aib^(8,27), β-Ala^(35,37), Arg³⁸, Lys³⁹(N^(ε)-octanoyl))hGLP-1(7-39)NH₂ EXAMPLE 407 (Aib⁸, Arg^(26,34), β-Ala³⁵, Lys³⁷(N^(ε)-octanoyl))hGLP-1(7-37)NH₂ EXAMPLE 408 (Aib⁸, Arg^(26,34), β-Ala³⁵, Lys³⁷(N^(ε)-decanoyl))hGLP-1(7-37)NH₂ EXAMPLE 409 (Aib⁸, Arg^(26,34), β-Ala³⁵, Lys³⁷(N^(ε)-tetradecanoyl))hGLP-1(7-37)NH₂ EXAMPLE 410 (Aib⁸, Arg^(26,34), β-Ala³⁵, Lys³⁷(N^(ε)-dodecanoyl))hGLP-1(7-37)NH₂ EXAMPLE 411 (Aib⁸, Arg^(26,34), β-Ala³⁵, Lys³⁷(N^(ε)-dodecanoyl))hGLP-1(8-37)NH₂

Physical data for a representative sampling of the compounds exemplified herein are given in Table 1. TABLE 1 Example Mol. Wt. Mol. Wt. Purity Number Expected MS(ES) (HPLC) 24 3351.8 3352.2   88% 26 3340.17 3340.9   99% 27 3353.81 3353.9   99% 29 3353.81 3353.9   99% 45 3352.6 3352.5   97% 51 3326.74 3326.6   99% 78 3395.81 3395.5   96% 136 3494 3494   99% 364 3523.02 3523.6   99% 365 3580.13 3580.3   95% 369 3677.25 3677   97% 370 3692.28 3692.4   98% 371 3807.37 3807.3   98% 372 3579.11 3579.7 97.90% 373 3337.81 3338.5   94% 374 3779.3 3779.5   94% 375 3297.7 3297.5   99% 376 3327.7 3327.4   98% 377 3398.8 3398.7 97.50% 378 3311.6 3311   93% 379 3366.85 3366.5   97% 380 3309.8 3309.4   99% 381 3354.8 3354.5 97.70% 382 3350.9 3350.3 97.20% 383 3311.73 3310.7   92% 384 3481.95 3481.3 94.30% 385 3281.76 3281.6   98% 386 3509.02 3509.1 99.40% 387 3665.2 3665.1   99% 388 3365.91 3365   97% 389 3324.79 3324.2   95% 390 3539 3539.2   93% 391 3381.74 3381.3   97% 392 3410.89 3409.8   99% 393 3481.95 3481.1   90% 394 3286.76 3286.2 99.20% 395 3300.76 3299.4   93% 396 3350.81 3349.4   99% 397 3400.87 3400.1   99% 398 3406.84 3406.4   99% 399 3356.77 3356.6   99% 400 3384.87 3384.43   94% 401 3400.87 3401.3   99% 402 3466.03 3466.9 97.40% 403 3522.05 3522.06   93% 404 3550.11 3550.2   98% 405 3567.09   99% 406 3763.38 3763.2   95% 407 3636.15 3635.8   99% 408 3664.21 3663.3   99% 409 3720.32 3719.5   99% 410 3692.27 3691.7   99% 411 3555.13 3554.4   99% 

1-9. (canceled)
 10. A compound of the formula: [Aib^(8,35)]hGLP-1(7-36)NH₂   (SEQ ID NO:2), pharmaceutically acceptable salt thereof.
 11. A pharmaceutical composition comprising an effective amount of a compound according to claim 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
 12. A method of eliciting an agonist effect from a GLP-1 receptor in a subject in need thereof which comprises administering to said subject an effective amount of a compound according to claim 10 or a pharmaceutically acceptable salt thereof.
 13. A method of treating a disease selected from the group consisting of Type I diabetes, Type II diabetes, obesity, glucagonomas, secretory disorders of the airway, metabolic disorder, arthritis, osteoporosis, central nervous system disease, restenosis and neurodegenerative disease, in a subject in need thereof which comprises administering to said subject an effective amount of a compound according to claim 10 or a pharmaceutically acceptable salt thereof.
 14. A method according to claim 13 wherein said disease is Type I diabetes or Type II diabetes. 15-18. (canceled) 